>> GREETINGS, EVERYONE. WE'RE
GOING TO GET STARTED. TODAY
(INAUDIBLE) ARE GOING TO THE
HANG THE REIGNS TEMPORARILY TO
WILL BOHR AND HE WILL INTRODUCE
OUR SPEAKER. TAKE IT AWAY.
>> THANK YOU, CAROLYN. IT IS A
PLEA TOWER TO INTRODUCE
SCHUMACHER, OLD FRIEND OF MINE.
BEFORE I DO THAT I WANT TO
REMIND EVERYONE THAT THE
QUESTIONS ARE PUT IN THE CHAT
AND THEN WE READ THEM FORBORNE
AND HE WILL ANSWER QUESTIONS
FOLLOWING THAT. BJORN IS VERY
WELL KNOWN IN OUR FIELD OF AGING
AND GENOME INSTABILITY. HE IS
NOW PROFESSOR AND DIRECTOR OF
THE INSTITUTE FOR GENOME
STABILITY AND AGING DISEASES.
AND CECAD CENTER THERE AS WELL.
HE RECEIVED HIS Ph.D. FROM THE
MAX PLANK INSTITUTE IN MUNCIEON.
THEN A POST-DOCTORAL FELLOW IN
ROTTERDAM WHERE HE DID IMPORTANT
MOUSE WORK. HE'S CURRENTLY
PRESIDENT OF GERMAN SOCIETY FOR
DNA REPAIR, CO-DIRECTOR OF THE
MINERVA CENTER OF BIOLOGICAL
MECHANISMS OF HEALTHY AGING AT
(INAUDIBLE) UNIVERSITY AND WAS
ALSO THE PRESIDENT OF THE
JOURNAL SOCIETY FOR AGING
RESEARCH. AND IN ADDITION TO ALL
HIS WORK ON GENOME INSTABILITY
WHICH IS VERY IMPORTANT WORK HE
HAS ALSO WRITTEN BOOKS ABOUT
AGING RECENTLY A COUPLE OF YEARS
AGO A VERY INTERESTING VERY
COMPREHENSIVE BOOK ABOUT THE
AGING PROCESS THAT WAS WIDELY
REFERRED AND SOLD. HE HAS WORKED
ON MAMMALIAN SYSTEMS AND
CELLULAR SYSTEMS AND ON
NEMATODES AND HAS RECENTLY
DISCOVERED THE GENE COMPLEX
IMPORTANT IN DNA REPAIR IN MANY
OTHER VERY IMPORTANT ASPECTS OF
DNA REPAIR RELATING TO THE VERY
BROAD IMPLICATIONS OF DNA DAMAGE
AND REPAIR. SO WE ARE REALLY
PLEASED TO HAVE YOU BJORN AND WE
LOOK FORWARD TO YOUR
PRESENTATION. THANK YOU.
>> YOU ARE MUTED BJORN.
>> NOW YOU SHOULD BE ABLE TO
HEAR ME. SORRY. SO MUCH FOR THIS
VERY KIND INTRODUCTIONS, THIS
WONDERFUL WORDS. I'M VERY
PLEASED TO SPEAK TO YOU TODAY
ABOUT GENOME STABILITY AND HOW
IT AFFECTS AGING. AND
INHERITANCE AND HOW THESE TWO
PROCESSES ARE REALLY
INTERTWINED. IN PARTICULAR WHAT
WE CAN LEARN FROM SIMPLE MODEL
ORGANISMS THAT WE BELIEVE HAS
RELEVANCE FOR HUMAN HEALTH AND
DISEASE. IS THIS NOT ADVANCING?
USE THE ARROW.
>> YOU ARE AWARE WE ARE LIVING
IN THE MIDST OF THE DEMOGRAPHIC
CHANGE THAT STARTED ABOUT 150
YEARS AGO, SINCE THEN LIFE
EXPECTANCY OF HUMANS HAS
DOUBLED. AND THIS IS NOT ONLY
RESTRICTED TO WESTERN EUROPE
NORTH AMERICA BUT IT IS A REALLY
WORLDWIDE PHENOMENON. WITH THE
HIGH LIFE EXPECTANCY AND LOW
MORTALITY OF MODERN SOCIETY WE
REALLY HAVE ENTERED A PHASE
WHERE THE PROPORTION OF ELDERLY
HAS STEEPLY INCREASING AND WILL
SOON BE 30% AND MORE OF OUR
POPULATION WITH AGE ABOUT 60.
AGING HOWEVER COMES INVARIABLY
WITH DISEASE, WITH MULTIPLE
CHRONIC DISORDERS RELATED FROM
DEMENTIA WITH ALZHEIMER THE MOST
PRESENT FORM, CARDIOVASCULAR
DISEASE THAT STILL ARE THE
NUMBER ONE KILLER ES. CHRONIC
KIDNEY DISEASE, SEVERE CLINICAL
PROBLEM, TYPE 2 DIABETES ON THE
RISE, WITH MACULAR DEGENERATION
IN LARGE PROPORTION OF THE
POPULATION. A SINGLE BIGGEST
RISK FACTOR FOR CANCER MORE THAN
ANY GENETIC OR ENVIRONMENTAL
FACTOR IS AGE. WHAT IS MORE IS
THE DISEASES OF AGING SELDOM
COME ALONE. IN FACT,
MULTI-MORBIDITY IS THE TRUE
DISEASE OF AGING. MULTI-MOSHED
INCREASES AFTER THE FIFTH DECADE
OF LIFE AND THAT MEANS WE HAVE
AN EVER GROWING POPULATION THAT
SUFFERS FROM MULTIPLE CHRONIC
DISEASE. MORE THAN HALF THE
ELDERLY SUFFER FROM THIS.
ALREADY NOWADAYS WE ARE SPENDING
50% OF HEALTHCARE COSTS ON THE
ELDERLY AND BY 2050 WE HAVE 2
BILLION PEOPLE ABOVE AGE 60. THE
TRADITIONAL APPROACH THOSE
DISEASES HAS BEEN DISEASE
SPECIFIC THERAPIES. IN ORDER TO
IMPROVE TREATMENT FOR DEDICATED
CANCER RESEARCH TRYING TO
UNDERSTAND THE BIOLOGY OF CANCER
AS YOU ARE WELL AWARE, WE HAVE
COME THROUGH PERSONALIZED
MEDICINE TO PRECISION MEDICINE,
TO ALWAYS MORE AND MORE
SPECIFICALLY TREAT THE SPECIFIC
CANCER TYPE. THIS IS ALSO
INCREASINGLY TRUE FOR
CARDIOVASCULAR DISEASE, DEMENTIA
FORMS, SO ON. SPECIALIZED
TREATMENTS. BUT IF YOU ARE NOW
TAKE THESE CHRONIC DISEASE OF
AGING TOGETHER WITH THE
DEMOGRAPHIC CHANGE, THIS WOULD
MEAN YOU WILL HAVE ONE
HOSPITALIZATION OF THE OTHER,
ONE TREATMENT AFTER THE OTHER,
FOREVER INCREASING PROPORTION OF
THE POPULATION. MODERN AGING
BIOLOGY HAS CHANGED THE PARADIGM
AND IS POSTULATING THAT NOT ONLY
CORRELATED TO THIS DISTINCT
DISEASE TYPES BUT IN FACT IS THE
ROOT CAUSE. INSTEAD OF TREATING
DISEASE ONCE THEY OCCUR, AGING
RESEARCH IS TRYING TO DIRECT
GENERAL PROTECTIVE TREATMENT AT
THE AGING PROCESS IN ORDER TO
PREVENT AT LEAST DELAY ONSET OF
AGE RELATED DISEASES. THIS MOST
CERTAINLY UNDERSTAND REQUIRES WE
UNDERSTAND MECHANISMS THAT
UNDERLIE THE AGING PROCESS.
FUNDAMENTAL MECHANISM THAT
DRIVES THE AGING PROCESS IS
DAMAGE TO THE GENOME. WHILE THE
GENOME CONTAINS ALL INFORMATION
HOW TO BUILD AND MAINTAIN
ITSELF, IT IS SURPRISINGLY
UNSTABLE. IN FACT EXPOSED TO
EXOGENOUS AND ENDOGENOUS DAMAGE
TYPES, EVERY SINGLE DAY OF YOUR
LIFE. EVERY SINGLE CELL IN YOUR
BODY IS EXPOSED TO TENS OF
THOUSANDS OF DAMAGING EVENTS.
AND THEY CAN COME IN A DISTINCT
DAMAGE TYPES DEPENDING ON THE
GENOTOXIC INSIGHT AND HOW IT
INTERACTS WITH SPECIFIC PARTS OF
THE GENOME. THIS DIFFERENT
DAMAGE TYPES HAS ESSENTIALLY TWO
DISTINGUISHABLE MOLECULAR
CONSEQUENCES. THE ONE WE
UNDERSTAND WELL IS HOW DNA
DAMAGE LEADS TO TRANSLOCATION
MUTATIONS DELETIONS AND THEY ARE
KNOWN MANY DECADES TO BE CAUSE
FOR CANCER. BUT DNA DAMAGE
CANNOT BLOCK TRANSCRIPTION
REPLICATION, THIS LEADS TO CELL
FATE ALTERATION. THE DNA DAMAGE
RESPONSE THAT CAN INDUCE APOT
POP TOTTIC CELL DEATH CELLULAR
SENESCENCE THIS LEVERS TO STEM
CELL COMPARTMENTS, ALL THESE
CELL FATE ALTERATI ALTERATIONS O
FUNCTIONAL DECLINE AND ATROPHIC
AND SYSTEMIC O SO DNA DAMAGE IS
A FUNDAMENTAL CAUSE THAT
PROMOTES THE AGING PROCESS. DNA
REPAIR MECHANISMS HAVE EVOLVED
EARLY IN THE EVOLUTIONARY
HISTORY BECAUSE THEY WERE
ABSOLUTELY ESSENTIAL FOR
ALLOWING STAGE REPLY KAY TORRS
INITIALLY -- REPLICATORS AND
PREVENTING MOLECULAR
CONSEQUENCES. HERE I SHOW
EXAMPLES OF THE DISTINCT
CONSEQUENCES OF DEFECTS IN DNA
REPAIR. ON THE ONE SIDE YOU SEE
HERE CHILD BORN WITH CONDITION
CALLED PIG MEN TOE SUM AND --
PIGMENTOSAM WITH SEVERAL
THOUSAND FOLD INCREASE SKIN
CANCER SUSCEPTIBILITY
ILLUSTRATING THE MUTAGENIC
CONSEQUENCE OF DNA DAMAGE. ON
THE OTHER SIDE YOU SEW A BOY WHO
SUFFERS FROM COCKAYNE SYNDROME,
A PREMATURE AGING CONDITION
WHERE INITIALLY SEVERE GROWTH
DELAY IS DETECTED, AND FUNNELED
BY MULTIPLE JOE GENERATIVE
HISTONES LET LAR DEGENERATION,
ATHEROSCLEROSIS, PATHOLOGIES
THAT WE ARE EXPERIENCING ONLY AT
VERY OLE AGE. HERE ALREADY
WITHIN THE FIRST DECADE OF LIFE
EXEMPLIFYING THE DEGENERATIVE
CONSEQUENCES OF DNA DAMAGE. NOW
WHEN WE WANT TO UNDERSTAND ANY
PROCESS IN BIOLOGY, WE NEED TO
UNDERSTAND HOW THIS PROCESS
EVOLVED IN THE EVOLUTIONARY
HISTORY. HERE A FUNDAMENTAL
CONTRIBUTION TO UNDERSTANDING
THE ULTIMATE CAUSES OF AGING
CAME FROM A ZOOLOGIST WHO IN THE
LATE 19TH CENTURY WAS ONE OF THE
TOP EVOLUTIONARY BIOLOGISTS.
WHAT WISEMANN PROPOSED WAS THE
GERMPLASM THEORY, THE THEORY OF
INHERITANCE WE HOLD TRUE UP TO
THIS DAY. WHAT HE REALIZED IS
INHERITABLE TRAITS EXCLUSIVELY
PASSED ON BY GERM SETS. WHAT WAS
LATER KNOWN AS THE WEISMANN
BARRIER, DESCRIPTION OF THE
PROTECTION OF HERITABLE GENOMES
FROM SOMATIC ENVIRONMENT
INFLUENCES. WHAT PASS ON GENETIC
INFORMATION THROUGHOUT THE
GENERATIONS. AND WHEN THEY
DEFINITELY DO SO, THEY REQUIRE
IN A DEFINITE GERM LINE
MAINTENANCE. THE STOMA INSTEAD
ONLY NEEDS TO BE MAINTAINED FOR
AS LONG AS IT TOOK IN
EVOLUTIONARY HISTORIC TIMES TO
ESTABLISH THE NEXT GENERATION.
ONCE THE GENES ARE SAFELY PASSED
ON, THE STOMA CAN DECAY AGE AND
DIE. THIS ULTIMATELY WHY WE AGE.
WE ARE NOTHING MORE THAN THE
MERE VEHICLES OF OUR GERM CELLS.
THIS MEANS THE GENOME STABILITY
IN GERM CELLS IS THE
PREREQUISITE FOR FOR UNTILTY,
GERM LINE AND SPECIES
MAINTENANCE. FERTILITY. WHAT IS
INTERESTING FOR US TO UNDERSTAND
HOW GERM CELLS MANAGE TO
INDEFINITELY MAINTAIN THEIR
GENOMES THROUGHOUT THE
GENERATIONS. BUT GERM CELLS COME
IN DIFFERENT FLAVORS. AS Y'ALL
KNOW, THE FEMALE GERM CELLS
PROVIDE MORE CYTOPLASMIC
COMPONENTS AND ORGANELLES AND
THE FEMALE GERM CELLS
PREDOMINANT SOURCE OF ANI PLOIDY
ON THE GENOME CELL, AANYPLOIDY,
TRISOMY 21, THE BIGGEST RISK
FACTOR IS MATERNAL AGE. MANY
GERM CELLS DO SOMETHING
FUNDAMENTALLY DIFFERENT. MALE
GERM CELLS ARE IN FACT THE
PREDOMINANT SOURCE OF MUTATIONS.
BOTH SINGLE NUCLEOTIDE STRUCTURE
VARIANCE 80% WHICH ARE GENERATED
IN H THE MALE GERM LINE, NOT THE
FEMALE GERM LINE. SO THEY ARE
FUNDAMENTAL DIFFERENCES. WE ARE
INTERESTED IN UNDERSTANDING THE
CONSEQUENCES OF PATERNAL DNA
DAMAGE BECAUSE THE PATERNAL
GENOME IS SUCH AN IMPORTANT
SOURCE FOR GENETIC ABOUT BEAR
RATIONS. THIS PROJECT WAS
PIONEERED BY CR 1 AND
BIOINFORMATICS ANALYSIS WAS DONE
BY DAVID (INAUDIBLE) IN THE LAB.
THAT'S SOME HINTS THAT COULD BE
CONSEQUENCES OF PATERNAL DNA
DAMAGE. FOR EXAMPLE, THE RISK OF
NEURODEVELOPMENTAL DISORDERS
SUCH AS AUTISM AND SCHIZOPHRENIA
IS LINKED TO CHROMOSOME
STRUCTURE BOUNDS. THE LAST
DECADES WE HAVE SEEN A STEEP
INCREASE IN AUTISM CASES THAT
ARE FOR WHICH THE BIGGEST RISK
FACTOR IS THE PATERNAL AGE.
THERE IS A LONG DEBATE A DECADE
OLD DEBATE WHETHER THERE IS
INCREASED LEUKEMIA RISK IN
RADIATION EXPOSED PRODUCTS. MOST
RECENTLY, THE UK GENOME PROJECT
FOUND RARE CASES OF HYPERMUTATED
GERM LINE GENOMES. ,
HYPERMUTATED GERM LINE GENOMES
IN HUMANS WERE ASSOCIATED WITH
GENOTOXIC INFLUENCE OF THE
FATHER, AT CLOSE TO CONCEPTION
SO FOR EXAMPLE, WHEN THE FATHER
UNDERWENT CHEMOTHERAPY. SO
THERE COULD BE SOMETHING TO IT.
TO RESOLVE THIS ISSUE, WHAT
CONSEQUENCES PATERNAL DNA DAMAGE
COULD HAVE? WE TURN TO C
ELEGANS. THOSE FAMILIAR WITH
THE C ELEGANS SYSTEM MIGHT BE
SURPRISED THAT WE ARE STUDYING
CONTRIBUTION OF DIFFERENT SEXES
IN AN ANIMAL THAT IS NORMALLY
HER HALF INDICT. WE CAN TAKE
ADVANTAGE OF SEX DETERMINATION
MUTANTS FEMALE ONLY GERM LINE
MUTANTS, WHERE WE CAN HAVE
SEPARATE SEX FEMALES WITH THE
FEMALE GERM LINE AND NORMAL
MALES WITH A MALE GERM LINE. WE
DID A VERY SIMPLE EXPERIMENT. WE
TREATED THE FEMALES WITH
IONIZING RADIATION AND RIGHT
AFTER THE MATE LET THEM MATE
WITH HEALTHY MALES THEN WHEN HE
ASK CALLED DELTA F FOR THE
FEMALES IRRADIATED AND ASK HOW
MUCH LETHALITY WOULD BE OBSERVED
IN THE PROGENY? AS YOU CAN SEE
HERE WITH INCREASES DOSESES OF
IONIZING RADIATION THAT PROGENY
SHOWS INCREASE LETHALITY, JUST
AS EXPECTED. THE SURVIVES OF
THESE ANIMALS WHICH WOULD BE THE
DAUGHTERS, THEREFORE THE SONS WE
THEN MADE GET HEALTHY OPPOSITE
SEX AND AGAIN, THEN IT SAYS THE
LETHALITY AMONG PROGENY, THEY
WERE ON HEALTHY ENVIRONMENT. SO
THIS IS ALL AS EXPECTED. BUT
THEN WE IRRADIATED MALES AND
DELTA M, WE IRRADIATED MALES AND
MATED THEM WITH HEALTHY FEMALES,
BUT IN THIS CASES WE OBSERVED
NEARLY NO LETHALITY THEIR
PROGENY THOUGH THE MALES HAD
EXPERIENCED THE SAME DOSE OF
RADIATION. WE THEN MADE A DOSE
DAUGHTERS, OR SONS WITH HEALTHY
OPPOSITE SEX. UNEXPECTEDLY WE
THEN OBSERVE IN THEIR PROGENY
ENORMOUSLY HIGH DEGREES OF
LETHALITY, THIS WAS HIGHER IN
THE OFFSPRING OF DAUGHTERS THAN
THE OFFSPRING OF THE SONS BUT IN
BOTH CASES WE OBSERVED IT. THE
DIFFERENCE I CAN EXPLAIN TO YOU
LATER ON. WE THEN ASKED WHETHER
THERE WAS A SPECIFIC STATE IN
SPERMATOGENESIS THAT WOULD BE
VULNERABLE TO THE
TRANSGENERATION OF LETHALITY. SO
AGAIN, WE IRRADIATED THE MALES
MATED IT DIRECTLY WITHIN THE
HEALTHY FEMALE AND OBSERVE THE
HIGH LEVEL OF PROGENY LETHALITY
IN THE PROGENY OF THE DAUGHTER
AND THE SONS. WE CON TERMED
THAT ALSO INDEPENDENT FEMINIZED
MUTANTS THAT THE SAME OCCURS.
THEN WE TOOK THIS MALE A DAY
LATER AND MATED IT AGAIN. C
ELEGANS LIKE HUMANS HAVE
CONTINUOUSLY UNDERGONE
SPERMATOGENESIS. THEY STORE
THEM IN EJACULATE 70% IN ONE
MATING AND BY THIS TIME THEY
WOULD HAVE NOW NEWLY GENERATED
FROM STEM CELLS NEWLY GENERATED
SPERM THEY USE ON THE SECOND DAY
NOR THEIR MATING. WE SEE NO
LETHALITY IN THE OFFSPRING OF
THE DAUGHTERS AND SONS
SUGGESTING THAT ONLY THE MATURE
SPERM IS VULNERABLE TO THE DNA
DAMAGE BY THE NEWLY GENERATED.
THEN WE ASK IF THIS ALSO HAPPENS
IN THE HERMAPHODITE THEY SWITCH
THE SEX OF GERM LINE, INITIALLY
GENERATE SPERM WITH LAVA
DEVELOPMENT, THIS THE THIRD
STAGE THEY HAVE SPERMATOGENESIS,
ALSO IN EARLY L 4 STAGE THE
FINAL STAGE ONGOING
SPERMATOGENESIS, ONE OF THE LATE
STAGE ON SPERM MATURE NOW, WHILE
GERM LINE NOW HAS SWITCHED TO
PRODUCE OO CITES THAT ARE THEN
FERTILIZED BY THE MATURE SPERM.
ONLY IN THIS CASE WE SEE
TRANSGENERATION LETHALITY
FURTHER SUPPORTING ITS MATURE
SPERM. THEN WE ASK HOW LONG
WOULD IN BE MAINTAINED, THIS
TRUNK GENERATION OF LETHALITY IN
HALF INDICTS IN CONTRAST TO
MATING OF EXPERIMENTS FROM
HEALTHY GENOME OF OPPOSITE SEX
BUT USING THE DAMAGED GENOME FOR
SELF-FERTILIZATION AND
ESSENTIALLY MAINTAINED FOREVER.
THE FEW RARE SURVIVORS THEY GIVE
RISE TO VERY HIGH LEVELS OF
LETHALITY IN THE PROGENY AGAIN.
NEXT, HAVE A LOOK WHAT HAPPENS
TO THE DAMAGE GENOMES IN THE
MATURE SPERM. NORMALLY MATURE
SPERM MANY WORMS JUST LIKE
HUMANS IS HIGHLY COMPACT. WE SEE
THESE STRUCTURES HIGHLY
COMPACTED DNA. AFTER IRRADIATION
HOWEVER THE SHAPE OF THESE
COMPACTED IS CHANGED AS IF THEY
ARE DECOMPACTING DECONDENSING.
NONETHELESS DESPITE THE DAMAGE
WE INFLICT, THEY FERTILIZE AN
EGG, FORM A ZYGOTE AND GROW UP
TO EMBRYO OWE THEN GO TO RAPID
ROUNDS OF CELL DIVISIONS BUT IN
CONTRAST TO CONTROL WE SEE HERE
FIGURES OF GENOME INSTABILITY.
WE SEE MICRONUCLEI, WE SEE
NON-DESTRUCTION OF DNA HERE AND
DESPITE ALL THESE GENOME
INSTABILITY THESE EMBRYOS GROW
UP TO ADULT WORMS. WE LOOK HERE
NOW AT THE STOMA OF THE PROGENY
AND WHEREAS INTESTINAL CELLS
EASILY VISIBLE LARGE CELL TYPES
THEY STILL SHOW SIGNS OF GENOME
INSTABILITY. SO AFTER
PERPETUATING -- PERPETUAL CYCLES
OF CELL DIVISIONS STILL THEY
HAVE EVER ONGOING GENOME
INSTABILITY. NOW BELOOK AT GERM
LINE OF DAUGHTER OF IRRADIATED
MALE. WE LOOK AT THE GERM LINE
AND WE SEE IN THE GERM CELLS
AGAIN OVERT SIGNS OF GENOME
INSTABILITY, YOU SEE
MICRONUCLEI. IN THE OO CITES, WE
SEE OBVIOUS SIGNS AGAIN
FRAGMENTS OF DNA, SOME HAVE
TELOMERE, OTHERS DON'T SO
THERE'S ONE OOCITE AND YOU SEE
ABERRANT FIGURES OF THE
CHROMOSOMES. THEN WE LOOK WHAT
HAPPENED -- WHAT HAPPENS TO THE
SEQUENCE OF THESE PROGENIES? SO
WE DID WHOLE GENOME SEQUENCING
OF THE FATHERS, THE MOTHERS, THE
SONS AND DAUGHTERS AND THIS IS
JUST ONE EXAMPLE WED MANY MORE
AND OBSERVE THERE ARE FUSIONS
BETWEEN THE CHROMOSOMES. HERE
THESE ARE FUSION SITES, THESE
ARE EXAMPLES OF THAT, THERE ARE
ROUGHLY THE SAME NUMBERS IN
DAUGHTERS AN SONS BUT ONLY ONE
DIFFERENCE THAT ONLY THE
DAUGHTERS HAVE FUSIONS THAT
INVOLVE THE X CHROMOSOME. WHY IS
THAT? BECAUSE ONLY THE DAUGHTERS
FEMALES XX SO THEY HAVE ONE X
CHROMOSOME FROM THE FATHER AND
THE OTHER ONE FROM THE MOTHER
WHILE THE MALES XO ONLY HAVE X
CHROMOSOME FROM THE MOTHER. THIS
TELLS US THE FUSIONS ARE
GENERATED WITHIN THE PATERNAL
GENOME. NOW WE LOOKED AT THE
FUSION SITES AND ASKED IS THERE
ANY CERTAIN SPECIFIC PROPERTY
THAT WOULD TELL US WHAT IS GOING
ON HERE? WE FIND THAT IN THIS
FUSION SITE THERE IS A SPECIFIC
ENRICHMENT OF ONE NUCLEOTIDE
MICROHOMOLOGY. IN C ELEGANS ONE
NUCLEOTIDE MICROHOMOLOGY AT HUGH
SITE IS A TYPICAL HALLMARK OF
REPAIR MECHANISM WHICH IS
POLYMER RAISE MEDIATED ENJOINING
T AND EJ. SO LET'S DO THE
GENETICS AND FIND OUT WHETHER
TMEJ IS INVOLVED IN GENERATING
THESE FUSIONS. SO WHAT LOOKS
VERY BUSY HERE I WILL TAKE YOU
SLOWLY THROUGH. SO THESE ARE
JUST TWO DIFFERENT 60 AND 90
GRAY DIFFERENT IRRADIATION DOSE,
USE THE GERM LINE SO WE CAN HAVE
SEPARATE SEX. THEN WE
INACTIVATED BRACA 1 TO
INACTIVATE HOMOLOGOUS
RECOMBINATION REPAIR, WE
ACTIVATE NON-HOMOLOGOUS
ENJOINING OR WE ELIMINATE TMEJ
BY MUTATING THE POLYMERASE Q 1.
THEN WE OBSERVED THESE Q 1 TMEJ
DEFICIENT ANIMALS HAVE BEEN
ENORMOUSLY HIGH SENSITIVITY TO
IONIZING RADIATION. THE PROGENY
DIRECTLY OF THIS MALE IS
COMPLETELY LETHAL. FEW ANIMALS
GROW UP THEY DON'T DEVELOP A
GERM LINE SO IT IS TMEJ IS
ABSOLUTELY ESSENTIAL TO REPAIR
THE PATERNAL DNA DAMAGE. TMEJ
HAS SOME CONTRIBUTION, THERE'S
HERE YOU SEE INCREASED LETH
LETHALITY, HERE IN THE PROGENY
OF THE SON SO IT PLAYS SOME ROLE
NOT AS PROM INNOCENT AS T
MENTIONEREJ BUT HOMOLOGOUS
RECOMBINATION REPAIR YOU WOULD
EXPECT A MAJOR ROLE IN GERM
LINE, IS DISPENSABLE. THEN WE
ASKED WHO REPAIRS? IS IT FATHER
THAT EXPERIENCE IT IS DNA DAMAGE
OR THE MOTHER? WHERE SO WE SINCE
SEPARATED THE POLYQ 1 MUTANT.
BOTH PARENTS ARE HAVE A MUTATION
IN -- WE OBSERVE THAT WHEN THE
MALES ARE IRRADIATED AND MATED
THAT THERE IS A VERY HIGH DEGREE
OF LETHALITY. IN THE DIRECT
PROGENY. WHEN HOWEVER THE FATHER
WHO WE APPLIED THE DNA DAMAGE TO
IS PARQ 1 MUTATED WE SEE NO
EFFECT. WHENEVER HOWEVER THE
MOTHER HAS NO TMEJ WE SEE THE
SAME DEGREE OF LETHALITY IN THE
PROGENY. SUGGESTING THAT THE
MOTHER, MATERNALLY PROVIDED TMEJ
IS REPAIRING THE PATERNAL DNA.
NOW YOU MIGHT WONDER USING
IONIZING RADIATION WORKING IN
THE LAB DOES THIS HAPPEN IN
NATURE? SO WE USE 540 NATURAL
VARIANTS OF C ELEGANS THAT HAVE
BEEN SEPARATEED FROM THE LEFT
STRING FOR MILLIONS OF YEARS AND
ASKED WHETHER IN THE STRUCTURE
VARIANTS WE FINDS IN THESE MATES
IS THERE THE SAME MICROHOMOLOGY
PRESENTED, WE HAVE EXPECTED
PERCENTAGE AND WE HAVE A MUCH
HIGHER ENRICHMENT OF THE
MICROHOMOLOHOMOLOGY. WE FIND AGE
ONE NUCLEOTIDE MICROHOMOLOGY
TYPICALLY HALLMARK OF TMEJ. THEN
WE LOOK AT MUTATION ACCUMULATION
LINES SO THIS IS IN THE LAB
WHERE IN EACH GENERATION YOU
PICK A WORM AND THEN LET IT
ACCUMULATE RANDOM MUTATION
STRUCTURE VARIANTS IN THIS CASE,
OVER 40 GENERATIONS. AGAIN WE
SEE A STRONG ENRICHMENT OF THE
TMEJ AMONG THE STRUCTURE
VARIANTS. NOW YOU MIGHT WONDER
I'M NOT A WORM, DOES IT HAVE ANY
RELEVANCE FOR ME AS HUMAN? WE
TURN TO THE 1,000 GENOME PROJECT
IN THE HUMAN GENOME SEQUENCES
AND ASK WHETHER WE WOULD FIND
HERE AGAIN THE TMEJ SIGNATURE
AND WE DO, THERE IS AN OVERT
PRESENTATION IN HUMAN IT IS TMEJ
SIGNATURE IS 2 TO 6 NUCLEOTIDES
IN CONTRAST TO THE ONE
NUCLEOTIDE IN WORMS. SLIGHT
MECHANISTIC DIFFERENCE.
THEN WE ASKED WHETHER ALSO IN
HUMAN THIS IS IS AN EFFECT OF
THE PATERNAL GENOME. FOR THIS WE
TURN TO THE TRIO STUDY WHERE IS
THEY SEQUENCE MOTHER FATHER
CHILD, AND WE SEE ONLY IN THE
GENOMES THAT COME FROM THE
FATHERS AN ENORMOUS ENRICHMENT
OF THE MICROHOMOLOGY. THAT YOU
CAN SEE HERE THIS IS THE TYPICAL
TMEJ SIGNATURE, MICROHOMOLOGY
DIRECTED REPAIR IN HUMANS.
INDICATED THAT WHAT WE OBSERVE
HERE C ELEGANS IS OCCURRING IN
NATURE, AND IT IS OCCURRING
NATURALLY IN THE HUMAN
POPULATION, PARTICULAR --
SPECIFICALLY IN THE FARMS. WHAT
IS THE MECHANISM BEHIND THIS? WE
TURN TO A DISCOVERY APPROACH
WHERE WE JUST DID PROTEOMICS OF
PROGENY IRRADIATED AND WE SEE
STRONG INDUCTIONS OF THE PROTEIN
DNA COMPLEXES NUCLEOSOME
ASSEMBLY IN SHORT HISTONES.
AMONG THE HISTOSTONES WE SEE
ENORMOUS INDUCTIONS OF HISTONE H
1, H 1 IS HISTONE AND HIGH
LEVELS OF H 1 ASSOCIATED WITH
HETERO CHROMETYIZATION BECAUSE
THEY INCREASE THE COMPACTION OF
THE THE DNA. HISTONE H 1
RESPONSIBLE FOR THIS
TRANSGENERATION OF LETHALITY?
WHAT WE DO HERE IS WE NOW
ELIMINATE NON-CERTAIN SUB UNIT
OF HISTONE H 1 CALLED HIS 24 AND
PROGENY OF DAUGHTERS AND SON WE
SEE REVERSAL OF THE
TRANSGENERATION LETHALITY.
INDICATING INDEED THE HIGH H 1
INDUCTION OF H 1 LINKER IS
RESPONSIBLE. I TOLD YOU THAT
HIGH H 1 LINKER LEVELS WERE
LINKED TO HETERO CHROMATIN
FORMATION. WE LOOK HERE AT
MARKER OF HETERO CHROMATIN
DIMETHYLATION THAT IS NORMALLY
VERY, VERY LOW PRESENT IN THE
GERM LINE. HERE THE GERM LINE OF
THE DAUGHTERS OF IRRADIATED
FATHERS, WE SEE A STRONG
INDUCTIONS OF THE HETERO
CHROMATIN MARK. THIS IS A
CONSEQUENCE OF H 1 LINKER, HS 24
KNOCK DOWN, THAT PREVENTS
FORMATION OF THE HETERO
CHROMATIN AS WELL AS THE PROTEIN
H 1 SAME EFFECT. THIS IS TRUE
FOR THE DAUGHTERS AS WELL AS FOR
THE SONS. NORMALLY IN THE MALE
ONLY THE X CHROMOSOME IS HETERO
CHROMETIZE, HERE YOU SEE HETERO
CHROMATIN ALL OVER THE GENOMES.
THIS IS REVERTED IN HIS 21. WHAT
DOES HETERO CHROMATIN DO IN THE
GENOME AND DNA REPAIR? HETERO --
STRONG HETERO CHROMETYIZATION IS
KNOWN TO PREVENT ACCESS TO
HIGHLY EFFICIENT REPAIR
MECHANISM SUCH AS HOMOLOGOUS
RECOMBINATION REPAIR. NORMALLY
IN THE GAMMA MUTAGENESIS IN THE
ONGOING GERM LINE GENERATION IN
FEMALES AND MALES, HOMOLOGOUS
RECOMBINATION REPAIR IS
IMPROVED. DESPITE THE VERY HIGH
LETHALITY OF THE PROGENIES OF
THESE DAUGHTERS AND SONS OF
IRRIDIATED FATHERS WE SEE LITTLE
ENGAGEMENT OF RAD 51 MARKER FOR
RECOMBINATION REPAIR. WHEN WE
KNOCK DOWN H ISHS 24 HPL 1 WE
SEE STRONG ENGAGEMENT OF
HOMOLOGOUS RECOMBINATION WE
HYPOTHESIZE MIGHT RESOLVE THE
TRANSGENERATION LETHALITY BY
RESTORING STABLE GENOMES IN THE
DAUGHTERS AND THE SONS. THIS IS
INDEED THE CASE. AGAIN, WE DO
GENETICS. THE SLIDE LOOKS BUSY
BUT I TAKE YOU THROUGH. MUTANTS
MUTANT BACKGROUND, THEN WHAT WE
DO HERE, WE LOOK AT THE PROGENY
OF THE DAUGHTERS AND OF THE
SONS. WE SEE AGAIN VERY HYPO
LETHALITY IN THE PROGENIES HERE
WHEN WE THEN TAKE OUT HIS 24 HPL
1 WE SEE SIGNIFICANT REDUCTION
OF THIS LETHALITY. WHEN WE THEN
HOWEVER IN THE BACKGROUND OF
THESE ELIMINATION OF THE HISTONE
H 1 HETERO CHROMATIN PROTEIN,
WHEN WE THEN TAKE OUT BRACA 1
AND THUS PREVENT THE ENGAGEMENT
OF HR AGAIN, THEN WE REVERT THE
SUPPRESSION AND THEY ARE HIGHLY
SENSITIVE AGAIN INDICATING THAT
BY REDUCING HETERO CHROMATIN WE
CAN GAIN ACCESS TO HR AND LET
THEM FIX THE INHERITED GENOME
DAMAGE. WHAT DID I SHOW YOU
HERE? I SHOWED YOU THAT DAMAGE
IN MATURE SPERM IS NOT REPAIRED
LIKELY BECAUSE OF THE VERY HIGH
COMPACTION OF CHROMATIN MANY THE
MATURE SPERM, INSTEAD IT
FERTILIZES AN EGG. IT IS EXPOSED
TO MATERNALLY PROVIDED TMEJ THAT
REPAIRS THE BRIGHT BUG PRODUCES
STRUCTURE VARIANTS AND THEN THIS
STRUCTURE VARIANTS GIVE RISE TO
ONGOING GENOME STABILITY WE
PROPOSE THIS IS DUE TO THE
BREAKAGE CYCLE, EXACTLY WHAT
(INAUDIBLE) OBSERVED IN MICE IN
THE 1940s. ONGOING DNA DAMAGE
IN THE DAUGHTERS AND THE SONS
INCLUDING MANY THE GERM CELLS,
WHERE THE DAMAGE DNA IS HEAVILY
HETERO CHROMETIZED BY H 1
LINKER. THIS PREVENTS ACCESS OF
H -- HOMOLOGOUS RECOMBINATION
REPAIR AND THEN GIVES RISE TO
LETHALITY IN THE PROGENY WHICH
CAN BE REVERTED BY RESOLVING THE
HETERO CHROMETYIZATION AND
ALLOWING HR. HERE WE FOUND THE
INHERITANCE OF PATERNAL DNA
DAMAGE BY HISTONE DNA REPAIR
RESTRICTION THE DAMAGE SPERM
GENOME INSTABILITY OFFSPRING AN
TRANSGENERATIONALLY THAT WILLTY.
MATERNAL TMEJ IS MAJOR REPAIR
MECHANISM FOR PATERNAL DNA
DAMAGE BUT LEADS TO CHROMOSOME
REFUSION. PATERNALLY INHERITED
STRUCTURE VARIANTS IN HUMANS
CARRY THE SAME TMEJ SIGNATURE
SUGGESTING THIS IS A HIGHLY
CONSERVED MECHANISM. THE H 1
LINKER MEDIATES HETERO CHROME
TIP FORMATION AND PREVENTS
ACCESS OF HOMOLOGOUS
RECOMBINATION OF THE OFF
SPRIEST. THE TRANSGENERATIONAL
DNA DAMAGE CAN BE REPAIRED
UPONNEDLY LESION OF H 1 LINKER
HIS-24 THAT ALLOWS HOMOLOGOUS
RECOMBINATION REPAIR ACCESS.
THUS WE FIND UNDERPINNINGS OF
GERM LINE HYPERMUTATION IN
SPERM. NOW I WANT TO COME BACK
FOR THE LAST FEW MINUTES OF THIS
TALK TO OUR ORIGINAL THOUGHTS
ABOUT THE DISTINCTIONS BETWEEN
THE GERM LINE WITH THE
INDEFINITE GERM LINE MAINTENANCE
AND THE STOMA. DESPITE WHAT I
JUST SHOWED YOU THAT THERE ARE
GERM LINE MUTATIONS OTHERWISE WE
WOULDN'T HAVE (INAUDIBLE) AS
HUMANS THE SOMATIC MUTATION
RATES ARE MORE THAN ORDER OF
MAGNITUDE HIGHER THAN THE GERM
LINE MUTATION RATES. GENERALLY
GERM LINES ARE FAR BETTER AT
REPAIRING DNA THAN THE STOMA. SO
ARE THERE MECHANISMS THAT
RESTRICT SOMATIC DNA REPAIR?
THIS COMES -- BRINGS US TO THE
QUESTION WHETHER WE CAN ENHANCE
CAPACITY TO DNA REPAIR BY FOR
EXAMPLE, BRINGING THE SAME
REPAIR CAPACITY OF A GERM LINE
TO A SOMATIC CELL. THE PROBLEM
SO FAR INCREASING DNA REPAIR HAS
BEEN THAT HUNDREDS OF DISTINCT
DAMAGE TYPES THAT SIX MAJOR DNA
REPAIR SYSTEMS, AND MANY
ADDITIONAL ONES ASSOCIATED FOR
THESE DISTINCT DAMAGE TYPES AND
THUS FAR HIGHLY SPECIFICALLY OR
SINGLE REPAIR, GREATEST EXAMPLE
PHOTO LYSIS COULD BE IMPROVED SO
WE ASK THE QUESTION WHETHER
THERE ARE MASS REGULATORS OF DNA
REPAIR CAPACITIES. AS I SHOWED
YOU OUR PARADIGM THOUGHT WAS
HERE THAT THERE COULD BE
LIMITATION IN SOMATIC VERSUS
GERM LINE REPAIR. AS HUMANS A
WAY TO COMPLICATE IT AGAIN TURN
TO C ELEGANS WITH DISTINCT
BETWEEN GERM LINE AT SOMA ARE
EVIDENT AND SOME REPAIR
MECHANISM SUCH AS HOMOLOGOUS
RECOMBINATION GLOBAL GENOME
NUCLEOTIDE EXCLUSIVELY PRESENT
IN THE GERM LINE AND NOT THE
SOMA. EXTRAORDINARY GRAD STUDENT
(INDISCERNIBLE) IN THE LAB TOOK
THE -- APPROACHED THIS ISSUE BY
LOOKING NOW AT WHETHER WE COULD
FIND COMMON REGULATORS OF DNA
REPAIR GENES IN C ELEGANS. HE
COMPILED ALL THE DNA DAMAGE
RESPONSE STREAMS IN C ELEGANS
AND ASK WHETHER IN THEIR
PROMOTER SEQUENCE THERE COULD BE
ANY SPECIFIC MOTIF OVER PERSON.
T THIS APPROACH WAS MUCH EASIER
IN C ELEGANS THAN MAMMALS
BECAUSE PROMOTER STRUCTURE IS
SIMPLE. HE FOUND A SEQUENCE THAT
CDE CHR, THEY ARE BOUND BY A
TRANSCRIPTION REPRESSER COMPLEX,
SO CALLED DREAM COMPLEX THAT
STANDS FOR DIMERIZATION R
DROSOPHILA AND THEN ALSO IN C
ELEGANS. WHERE IT IS KNOWN IN C
ELEGANS THIS DREAM COMPLEX IS
SPECIFICALLY IN SOMATIC CELLS
BUT NOT IN THE GERM LINE. SO
HYPOTHESIS WAS THAT THIS DREAM
COMPLEX COULD BIND PROMOTER OF
DNA REPAIR GENES AND REPRESS
EXPRESSION. TO TEST WHETHER
DREAM MUTANTS COULD THEN CHANGE
RESISTANCE TO DNA DAMAGE, WE
PERFORMED DEVELOPMENTAL ASSAY.
WE TOOK NOW, WE ARE IN THE SOMA
NOW, WE ARE LOOKING AT L 1 WORMS
THIS IS THE FIRST LARVA STATE
WHERE 90% CELLS ALREADY
TERMINALLY DIFFERENTIATED AND
THEN JUST GROW IN SIZE TO FORM
ADULT ELEMENTS THROUGH THE L 1 L
2, L 3 L 4 LARVA STAGES. SO WE
SAID 48 HOURS LATER THE WORMS
HAVE GROWN UP TO YOUNG ADULTS,
ALL TREATED THE ANIMALS WITH DNA
DAMAGE WITH (INAUDIBLE) IN THIS
CASE AND ASK HOW MUCH DELAY
WOULD THERE BE BY THE DNA
DAMAGE. SO HERE WE SEE ABOUT IN
WILD TYPE ALMOST ALL THE ANIMALS
ARE STILL IN THE L 1 OR L 2
LARVA STAGE, DELAYED BUT
MUTATIONS THAT ABROGATE DREAM
FUNCTION IN 52 DPR 1 DIFFERENT
SUBUNITS, OR CONFIRM RESISTANCE
TO DNA DAMAGE, NOW THE ANIMALS
CAN GROW BETTER THAN WILD TYPE.
THIS IS A BONA FIDE FUNCTION OF
DREAM BECAUSE WHEN WE TAKE
SINGLE MUTANTS, THEIR RESISTANCE
HERE PROFICIENCY IN GROWING IN
CONTRAST TO WILD TYPE IS THE
SAME IN THE GENETIC -- IN
ADULTHOOD THERE IS ONE BIG
IMPORTANT DIFFERENCE BETWEEN
WORMS AND HUMANS, I SHOWED YOU A
HUMAN, ONE DNA REPAIR IS
SUFFICIENT TO ACCELERATE AGENING
THE SIMPLE NEMATODE, ONLY THREE
WEEKS WE NEED TO APPLY DNA
DAMAGE TO ACCELERATE AGE, WE DO
THIS HERE IN THE SOLID LINES
WHERE WE APPLY IN YOUNG
ADULTHOOD AND THEY ARE SHORT
LIVED BUT LIFE SPAN CONDITIONS
OF DNA DAMAGE SIGNIFICANTLY
EXTENDED BY DIFFERENT MUTATIONS
OF THE DREAM COMPLEX. DO THEY
REPAIR? IF YOU REINDUCE DIMER
PYRIMIDINE DIMERS WE HAVE
SIGNIFICANT ADVANTAGE THAT WE
CAN MEASURE THE DIMERS THE
DAMAGE WITH SPECIFIC MONOCLONAL
ANTIBODY. WE DO THIS HERE IN THE
SLOT PLOT WHERE YOU SEE VERY
INFLECTION IMMEDIATELY AFTER AND
THEY GET SLOWLY REPAIRED IN WILD
TYPE BUT MORE READILY REPAIRED
DPR 1 SO THEY REPAIR GENETICS
ARE IMPROVED. THIS IS IN 1
ANIMALS WE HERE LOOK AT ADULTS
LOOK AT THE HEAD REGION OF A
WORM, MOST CELLS ARE NEURONS IN
FACT. AND THEY ARE VERY, VERY
SLOW AT REPAIRING THE CPTs. WE
DO STAINING FOR CPTs AND LIMB
52 MUTANTS ARE REPAIRING FAR
SUPERIOR THAN THE WILD TYPE.
THEN WE ASK WE FOUND THIS DREAM
TARGET SEQUENCE IN SO MANY DNA
REPAIR GENES, DO THEY ALSO
REPRESS DNA REPAIR GENES IN
GENERAL? SO HERE WE COMPARE 52
MUTANTS WITH WILD TYPE IN RNA
SEQ AND WE SEE CONSISTENT WITH
MUTATING ACTIVATING
TRANSCRIPTION REPRESSER, MANY
GENES ARE INDUCED AND
DEREPRESSED, AMONG THOSE REPAIR
GENES. WHAT IS MORE IS WE FIND
REPAIR GENES NOW INDUCE THAT
OPERATE IN NUCLEOTIDE REPAIR IN
BASE SIBLING REPAIR HOMOLOGOUS
RECOMBINATION, NON-HOMOLOGOUS
ENJOINING SO A TRUE MASTER
REGULATOR OF DNA REPAIR
EXPRESSION THEN WE THOUGHT IF
THAT IS SO ANIMALS SHOULD BE
RESISTANT TO UV DAMAGE BUT ALL
TYPES OF DAMAGE. THIS IS WHAT WE
DESCRIBE HERE. WE USE IONIZING
RADIATION HIGH DOSE BECAUSE IT
IS POST MITOTIC CELLS GROWING IN
SIZE AND DEVELOPMENT AND WE SEE
THAT THERE IS A SIGNIFICANT
IMPROVEMENT RESISTANT IONIZING
RADIATION THAT IN THIS CASE IS
TOTALLY DEPENDENT ON
NON-HOMOLOGOUS ENJOINING. WE
ELIMINATE NON-HOMOLOGOUS
ENJOINING, NO SUCH DEFECT. WHEN
WE TEST ISOLATING LESIONS FOR
MMS WE SEE SIGNIFICANT
RESISTANCE CONFER IL 52. WHAT IS
INTERESTING IS WHEN WE TAKE A
HYPERSENSITIVE POLYMERASE MUTANT
THEN POLYH 1 MUTANTS ARE
HYPERSENSITIVE TO ISOLATING
LESION AND WE CAN SUPPRESS
BECAUSE OTHER REPAIR MECHANISMS
ARE -- CAN TAKE OVER BECAUSE
THEY ARE MORE ACTIVE. ALSO
CISPLATIN STILL IMPORTANT IN
CHEMOTHERAPY INDUCING AN
INTERESTING CROSS LINK IN 52
MUTANTS SHOW RESISTANCE. HERE IS
AN EXPERIMENT THAT GOT US REALLY
EXCITED. HERE INSTEAD OF THE
POST MITOTIC L 1 LAB THEY GROW
IN SIMILAR SIZE WE TAKE EARLY
EMBRYOS THAT WILL ONS GO THE
MOST RAPID ROUNDS OF REPLICATION
AT CELL CYCLE TO FORM THEN THE L
1 LAB. WHEN WE HOWEVER TREAT
THIS EARLY EMBRYO WITH IONIZING
RADIATION THE ANIMALS DIE. SO
WITH INCREASING ION, THE EMBRYOS
ARE DEAD. WHEN WE HAVE A 52
MUTANT THIS SENSITIVITY IS
REVERSED. THEY BECOME
RESISTANT. THE EARLY REPAIR
EARLY EMBRYOS IS EXECUTED BY
HOMOLOGOUS RECOMBINATION REPAIR.
WE ACTIVATE BRAC BARD THEN GET A
HYPERSENSITIVITY TO IONIZING
RADIATION JUST LIKE HUMAN
CARRIER CELLS BUT WE CAN REVERT
THE SENSITIVITY BY MUTATING LIN
52. OTHERS FROM MECHANISMS CAN
TAKE OVER, IN THIS CASE
NON-HOMOLOGOUS ENJOYING THAT
TAKES OVER BUT VICE VERSA, ALSO
HOMOLOGOUS RECOMBINATION REPAIR
IS MORE ACTIVE AND COMPENSATE
HERE FOR HOMOLOGOUS EFFECTS. NOW
AGAIN, YOU MIGHT ARGUE WORMS AND
HUMAN IS RELEVANT. THE DREAM
COMPLEX IS HIGHLY CONSERVED FROM
WORMS TO HUMANS. WE ASK WHETHER
IN THE TARGETS DEMONSTRATED TO
BE DIRECTLY TARGETED IN THE
PROMOTERS BY THE DREAM COMPLEX
REGULATED BY THE DREAM COMPLEX
WE ASK WHETHER AMONG THOSE GENES
THERE ARE DNA REPAIR JEANS AND
WE FIND SIGNIFICANT DNA REPAIR
GENE JUST LIKE IN C ELEGANS.
HUMANS ARE MORE COMPLICATED
DIFFERENT SUBUNITS CAN FUNCTION
AT OTHER COMPLEXES BUT THERE ARE
ALSO SOME ADVANTAGES IN HUMANS.
ONE BIG ADVANTAGE IS THAT WE
KNOW THAT THE DREAM COMPLEX IS
ASSEMBLED VIA THE CROSS
CORRELATION OF LIN 52 BY THE
JERC 1A KINASE. WHEN THAT IS
ABSENTS AND LIN 52 IS NOT
PHOSPHORYLATED THE DREAM COMPLEX
DISASSEMBLES AND NO LONGER
REPRESSES. FOR THE DIRK 1A
STUDIED IN MANY, MANY DIFFERENT
CIRCUMSTANCES, AND THERE ARE
INHIBITORS AVAILABLE. MOST
ESTABLISH THE NATURAL COMPONENT
WE USE IN ADDITION INDEPENDENT
CHEMICAL INHIBITOR. THE
HYPOTHESIS WAS THAT WHEN WE
INHIBIT DIRK 1A WE ALLEVIATE THE
DREAM FUNCTION AND THEN COULD
DEREPRESS AND MAYBE THIS IS A
STRATEGY TO PREVENT DEVELOPMENT
BY REDUCING ACCUMULATION OF
SOMATIC MUTATION AND PROMOTE
LONGEVITY BY KEEPING GENOMES
MORE STABLE. THIS IS WORK. SO
INITIALLY WE TOOK NOW QUIESCENT
HUMAN CELLS BECAUSE THE DREAM
COMPLEX IS ASSEMBLED IN G1 AND G
0 PHASES OF THE CELL CYCLE SO WE
TOOK QUIESCENT HUMAN CELLS AND
TREATED THEM WITH HARMINE SAND
FIRST ASKED IS BY INHIBITING
DREAM DYRK 1A THE DREAM
COMPLEXIN HINT? WE SEE
DEREPRESSION OF DREAM TARGET
GENES SO THEY ARE NOW IN USE.
MANY OF THESE ARE AFFECTIVE
REPAIR. THAT HYPOTHESIZES
LEADING TO DNA DAMAGE IS EXACTLY
WHAT HAPPENS. WE SEE LEAGUES
ISOLATING LESIONS, DIFFERENT
LESION TYPES NORMALLY WE SEE IN
QUIESCENT CELLS HIGH DEGREE OF
APOPTOSIS. BUT IT IS SUFFICIENT
TO TREAT THEM WITH HARMINE OR
THE SIGNIFICANTLY REDUCED
SENSITIVITY TO DNA DAMAGE. THE
VERY SAME WE OBSERVED IN C
ELEGANS. WE IMPLEMENT THAT IN
VIVO. SO THE PHENOTYPE THE
PATHOLOGY WE INITIALLY TOOK AS
PROOF OF CONCEPT WAS RETINAL
DEGENERATION. WHY? BECAUSE WE
KNEW THAT COCKAYNE SYNDROME, HAS
RETINAL DEGENERATION BY LOSS OF
PHOTO RECEPTOR CELLS, THIS
EQUIVALENT MOUSE WITH SAME
MUTATION MUCH MILDER THAN THE
HUMAN, THAT'S MOUSE SPECIFIC
THAT WE SEE THEY ARE SLOWER, BUT
WE SEE DEGENERATION. WE THEN ASK
WHETHER WE FIND IN ANY LINK IN
THE SPORADICALLY OCCURRING AGE
RELATED MACULAR DEGENERATION,
THESE ARE NORMAL PEOPLE THAT
DEVELOP AGE RELATED MACULAR
DEGENERATION WITH AGE AND WE
COMPARE THEIR RNA SEQ PROFILE
WITH AGE MATCH NON-HEALTHY
PEOPLE, RETINAS, AND ASK WHICH
TYPE OF GENES ARE UNDEREXPRESS
AND DOWN REGULATED AND WE FIND
HERE THAT TRANSCRIPTION COVERED
NUCLEOTIDE EXCISION REPAIR GENES
ARE DOWN-REGULATED IN THESE
HUMAN AMD PATIENTS AND IT IS THE
SAME PROCESS THAT IS INDUCED BY
CSB SUGGESTING THAT THE VERY
SAME MECHANISM DRIVE AGE RELATED
MACULAR DEGENERATION, AS DRIVES
RETINAL DEGENERATION IN CS
PATIENT. WE USED A MOUSE MODEL
HERE THAT IS AS SEVERE AS THE
HUMANS WHICH IS ESCC 1, FOR THIS
WE WORK TOGETHER WITH
(INAUDIBLE) AND THAT DID THE
EXPERIMENTS HERE. WHERE WE
TREATED THE PRODROID NER
DEFICIENT ANIMAL WITH HARMINE
AND WE KNEW THAT THE ERCC ONE
KNOCK OUT IN THE RETINA NUCLEAR
LAYER SHOWS APOPTOSIS IN PHOTO
RECEPTOR CELLS WHICH IS A DRIVER
OF MACULAR DEGENERATION. AND
THIS DEGENERATION THIS TUNNEL
POSITIVE CELLS ARE SIGNIFICANTLY
REDUCED BY THE HARMINE TREATMENT
SUGGESTING WE CAN CONFER
RESISTANCE TO DNA DAMAGE IN
VIVO. IS IT REALLY DNA DAMAGE?
SO HERE WE LOOK AT GAMMA H 2AX
IN RETINA YOU CAN REGULARLY SEE
IN A NUCLEAR LAYER, IT IS
ACCUMULATED IN THE SCC 1
ENDOGENOUS DNA DAMAGE, THIS IS
PREVENTED BY THE TREATMENT OF
HEARMINE INDICATING INDEED DNA
REPAIR IS INEPT. SO WE FOUND
HERE DREAM FUNCTION MASTER
REGULATOR OF DNA C ELEGANS
ELEVATE RESCISSION TANS TO DNA
DAMAGE BY IMPROVING SOMATIC
REPRESSION OF DNA REPAIR GENE
AND COMPARE GERM LION, THE DREAM
COMPLEXES INHIBITION AND
QUIESCENT HUMAN CELLS ELSE
INVESTIGATES RESISTANCE TO DNA
DAMAGE TYPES, THE DREAM IN VIVO
PROTECT IT IS RETINAL
DEGENERATION IN ERCC 1 MICE,
DREAM INHIBITION OFFERS
PHARMACOLOGICAL ROUTE FOR
ENHANCED GENOME MAINTENANCE TO
PREVENT REQUEST DNA DAMAGE
DRIVEN CANCER IN DEVELOPMENT AND
AGINAGING. I ACKNOWLEDGED THE PE
THAT DID THE WORK. WE ARE HIRING
POST DOCS AND REALLY HAPPY TO
TAKE ANY QUESTIONS. THANK YOU
VERY MUCH FOR YOUR ATTENTION.
I'M AVAILABLE FOR ANY QUESTIONS
YOU MAY HAVE. THANK YOU.
>> WONDERFUL LECTURE, REALLY
INTERESTING, GREAT WORK. DO WE
HAVE QUESTIONS IN THE -- AMONG
THE ATTENDEES HERE? KYNA ASKS,
GREAT DATA AND TALK. DOES
IRRADIATION OF MALES AFFECT THE
EXPECTANCY OF OFFSPRING?
>> WE HAVEN'T OBSERVED THAT IN C
ELEGANS. WHAT WE HAVE OBSERVED
IS THAT THE OFFSPRING SHOW SLIDE
DEVELOPMENTAL DELAY SO THERE ARE
PHENOTYPIC ALTERATIONS. SO FAR
WE HAVE NOT OBSERVED HOWEVER
THAT IT IS LIFE SPAN REDUCTION.
>> (INDISCERNIBLE)
>> WE HAVE A COMMENT BY
(INDISCERNIBLE) SAYING AMAZING
PRESENTATION. MICHAEL SAYS GREAT
TALK BJORN, DO YOU KNOW THE
TARGETS OF THE DYRK 1A ON HUMAN
CELLS CONTROLLED H EXPRESSION OF
DNA REPAIR GENES?
>> YEAH, SO IN DYRK 1A ACROSS
MULTIPLE TARGETS WE FIND IT
AFFECTIVELY INHIBITS INHIBITION
OF DYRK 1A EFFECTIVELY INHIBITS
THE DREAM COMPLEX, IT IS KNOWN
THAT DYRK 1A PHOSPHORYLATES LIN
52 IN A SPECIFIC SITE SERENE 1A,
SO THAT IS THE MECHANISM OF HOW
DYRK 1A AFFECTS DNA REPAIR
FUNCTION. AND OF COURSE DYR 1A
ITSELF ANY KINASE HAS ADDITIONAL
TARGETS, AND WE ARE CURRENTLY
EXPLORING HOW WE CAN
SUFFICIENTLY SPECIFICALLY
INHIBIT DYRK 1A TO BRING ABOUT
THE EFFECTS OF DREAM INHIBITION
TO INCREASE THE EXPRESSION OF
DNA REPAIR GENES.
>> OKAY. WE HAVE ANOTHER
QUESTION FROM MICHAEL. HE ASKS
DOES CISPLATIN CANCER HAVE
MUTATIONS IN DREAM COMPLEX?
>> THAT IS A VERY INTERESTING
QUESTION. .
WE DON'T KNOW, WE HAVEN'T LOOKED
AT THAT. T BUT I THINK THIS IS A
VERY EXCITING QUESTION TO ASK
BECAUSE THAT WOULD CERTAINLY
ALLOW CANCER CELLS TO BECOME
RESISTANTS IF THEY COULD
INCREASE DNA REPAIR FUNCTIONS.
THIS IS SOMETHING WE DEFINITELY
SHOULD LOOK AT.
>> PHILLIP SAYS BASED ON THE
MODEL I DON'T QUITE UNDERSTAND
WHY SECOND GENERATION IRRADIATED
FEMALES ARE HEALTHY.
>> SO FOR THE FEMALE, THEY CAN
DIRECTLY REPAIR AND THEN BE
HEALTHY, BUT DO NOT -- THEY USE
ACCURATE REPAIR MECHANISMS,
HOMOLOGOUS RECOMBINATION REPAIR.
SO WHATEVER IS BROKEN FROM
PROVIDED AS BROKEN DNA FROM AN
OOCITE THAT LEADS TO NOT
REPAIRED LEADS TO MITOTIC
CATASTROPHE DIRECTLY IN THE
EMBRYOS SO THE ONES THAT HAVE
UNRESOLVED DNA DAMAGE MAY JUST
DIE IMMEDIATELY OFF SO THEY DO
NOT GIVE RISE TO ANIMALS AT ALL.
WHILE IT IS ONLY THE FUSION
EVENTS THAT ARE GENERATED IN THE
PATERNAL DNA DAMAGE, DNA THAT
GIVES RISE TO THIS ONGOING DNA
DAMAGE BUT THEY DO NOT LEAD TO
MITOTIC CATASTROPHE DESPITE THE
ABERRANT MITOTIC FIGURES WE SEE
WITH NON-DISJUNCTION OF
CHROMOSOMES AND THINGS LIKE THAT
SO THAT IS THE MAJOR DIFFERENCE
SO FEMALES EITHER REPAIR OR THEY
ARE EMBRYONICALLY LETHAL
DIRECTLY.
>> WE HAVE A QUESTION FROM
(INAUDIBLE). HE SAYS I ADMIRE
YOUR BEAUTIFUL WORK. HE SAID
THAT THE DEFECTS IN HOMOLOGOUS
RECOMBINATION CAUSES CELL DEATH
DUE TO RADIATION AS A RESULT OF
NEGLECTING C ELEGANS. IS
NON-HOMOLOGOUS ENJOINING
ACTIVATED BY DSB IN C ELEGANS,
DOES IT NOT CONTRIBUTE TO
CHROMOSOME FUSION?
>> SO THAT IS SOME CONTRIBUTION
OF (INAUDIBLE) AS WELL SO WE DO
FIND NHJJ MUTANTS INCREASE LEVEL
OF TRANSGENERATION LETHALITY SO
THERE IS SOME FUNCTION OF NATJ
AS WELL BUT IT IS THE
PREDOMINANT REPAIR MECHANISM
APPEARS TO BE TMEJ.
>> (INDISCERNIBLE) SORRY IF I'M
MISPRONOUNCING YOUR NAME, SAYS
OVEREXPRESSION OR DISREGULATION
MAY OF MANY DNA REPAIR GENES
LEADS TO INCREASE GENOME
INSTABILITY DUE TO TOXICITY OF
DNA LESIONS GENERATING DURING
DNA REPAIR. DID YOU OBSERVE ANY
INSTABILITY IN MUTANT?
>> VERY INTERESTING QUESTION. WE
DO NOT. THE REASON WE BELIEVE IS
THAT WITH THE DREAM INHIBITION
OR ABROGATION WE SEE A
RELATIVELY MILD INCREASE IN
EXPRESSION OF DNA REPAIR GENE.
IT IS NOT HUGELY OVEREXPRESSED.
IT IS A RELATIVELY MILD BUT SO
MANY THE STOICHIOMETRY OF NORMAL
REPAIR MECHANISMS ARE STILL
MAINTAINED. IT APPEARS THAT WE
ARE REALLY HITTING A SWEET SPOT
THERE WHERE IT IS FUNCTIONING
BETTER BUT IT DOES NOT LEAD TO
ABERRANT REPAIR EVENTS THAT
WOULD BE DETRIMENTAL. THE -- SO
THE COORDINATION OF REPAIR
MECHANISMS SEEM TO BE REALLY
VERY WELL MAINTAINED. SO WE DO
NOT -- WE DON'T REALLY SEE
ADVERSE EFFECTS IN RELATION TO
THE DNA REPAIR CAPACITY.
>> WE HAVE A QUESTION FROM KYNA
ASKING MMS LESIONS ARE REPAIRED
BY BER, ARE DREAM MUTANTS BER
GENES ENZYMES UPREGULATED OR
ONLY SOME FOR EXAMPLE RATE
LIMITING STEP?
>> WE FIND SOME R GENES
DEREPRESS SO INDUCED IN THE
DREAM MUTANTS SO IT WOULD
SUGGEST THAT THAT INDEED IS
EXPLAINING THE ELEVATED
RESISTANCE TO MMS. WE HAVEN'T
REALLY VALIDATED WHICH OF THOSE
IS THE RATE LIMITING FACTOR IN
BR BUT THIS IS CERTAINLY
SOMETHING INTERESTING TO GO
AFTER.
>> IN THE HUMAN CELLS, MALE OR
FEMALE DO YOU SEE THIS
DIFFERENCE IN TMEJ PATHWAY?
>> VERY GOOD QUESTION. WE SEE IT
IN THE HUMAN GENOMES SO THAT
WOULD SUGGEST THAT ALSO IN
HUMANS IT IS REALLY THE TMEJ.
THIS HAS NOT HOWEVER YET BEEN
EXPLORED TMEJ IS ONLY BEEN
AROUND FOR ABOUT TEN YEARS
MAYBE. I THINK IT IS REALLY
UNDERINVESTIGATED. AND TURNS OUT
TO BE REALLY A MAJOR REPAIR
MECHANISM. NATURALLY OCCURRING
PATERNAL STRUCTURE VARIANCE IN
HUMANS WOULD SUGGEST EXACTLY
THAT THIS HAPPENS IN HUMANS AS
WELL.
>> THANK YOU.
>> BILL.
>> GREAT TALK. DO YOU KNOW HOW
GENES, 1A IS REGULATED WITH AGE?
>> GOOD QUESTION. WE DON'T KNOW
YET. WE GENERATED ACTUALLY NOW
NEW MOUSE MODELS FOR DREAM AND
THERE WE WILL EXPLORE THIS NOW
MUCH NOR THE MAMMALIAN SYSTEM AS
WELL. IT CERTAINLY IS VERY
INTERESTING QUESTION. ONE
INTERESTING RESULT, ACTUALLY
VERY EXCITING RESULT WE GOT NOW
FROM SUPER LONG LIVED MAMMALS,
SOME OF THE BAT SPECIESES THAT
ARE VERY LONG LIVED, THERE WE
FIND EXACTLY THAT DREAM TARGET
GENES ARE INDUCED THROUGH AGING,
THAT IS NOT HAPPENING IN HUMAN
AND MIC MICE. SO IT MIGHT VERY L
BE THAT CURBING DREAM FUNCTION
COULD HAVE BEEN A NATURALLY
EVOLVING MECHANISM FROM
MAMMALIAN LONGEVITY, THAT
SOMETHING WE ARE NOW
INVESTIGATING AND THINK WE ARE
VERY EXCITED ABOUT IT THAT IT
COULD BE REALLY SOMETHING THAT
NATURE HAS DONE IN THOSE
SPECIESES THAT ARE REALLY
EXCEPTIONALLY LONG LIVED.
>> IF YOU TREATED MOUSE WITH
HARMINE WITH INHIBITOR DOES THAT
GET PREMATURE AGING OR ANYTHING?
>> WE HAVE DONE THAT ONLY IN THE
SEC 1 MODEL BECAUSE IT IS
RAPIDLY DEGENERATING MODEL.
THERE WE CAN PREVENT THE
DEGENERATION SO SUGGESTING THIS
COULD WORK. HARMINE HAS BEEN
INDUCED IN PHASE 2 CLINICAL
TRIALS FOR TREATING TR TRISOMY ,
DYRK 1A IS LOCATED ON CHROMOSOME
21, OVEREXPRESSED IN DOWN'S
SYNDROME. SO MIGHT VERY WELL BE
THAT THE ELEVATED DYRK 1A
ACTIVITY COULD EXPLAIN SOME OF
THE PREMATURE AGING AND
NEURODEGENERATION IN DOWN'S
SYNDROME PATIENTS BECAUSE THEY
MIGHT THEN BECOME DEFISH IN
MULTIPLE DNA REPAIR MECHANISMS.
IN THESE TRIALS HARMINE DOESN'T
HAVE A SUFFICIENT SECURITY
OFFICERTY PROFILE. SO LIKELY
BECAUSE THEY ARE OFF TARGET
EFFECTS WITH RELATED KINASES
THAT HAVE SIMILAR ACTIVE SITES
AS DYRK 1A SO THAT IS WHY I
THINK THERE'S REALLY A LOT OF
IMPETUS NOW TO DEVELOP MORE
SPECIFIC INHIBITORS IN HARMINE.
>> SAFETY THING.
>> THERE IS A QUESTION FROM
(INDISCERNIBLE). WOULD YOU
EXPECT NON-DNA STRUCTURES SUCH
AS QUO TRIPLEXES TO BE A SIG DNA
DAMAGE? DOES IT CONTAIN DNA
REPAIR MECHANISM ACTING ON THIS
THESE, IF NOT EXTENDING
POLYMERASES SPECIALIZING IN
NON-DNA STRUCTURES ALSO PROTECT
AGAINST AGE SOMETHING
>> WE HAVEN'T YET LOOKED AT
THOSE STRUCTURE, VERY GOOD IDEA
WE KNOW HOWEVER YES INDEED
ALTERNATIVE POLYMERASES ARE
INDUCE IN THE DREAM MUTANTS. SO
SUGGESTING THAT THEY COULD
PROMOTE RESOLVING (INAUDIBLE)
THERE'S I THINK INCREASING
EVIDENCE THAT (INAUDIBLE) ARE
NATURALLY -- THEY ARE NATURALLY
OCCURRING. AND THEY MIGHT BE A
DRIVER OF GENOME INSTABILITY FOR
EXAMPLE, THEY CAN PROMOTE
FORMATION OF RNA TRANSCRIPTION
WHICH IS A SIGNIFICANT SOURCE OF
ABERRANT GENOMIC STRUCTURE. SO
IT IS VERY INTERESTING TO
EXPLORE THIS FURTHER. IN
PARTICULAR THE INVOLVEMENT OF
THE INDUCED TLS THAT WE DO SEE.
>> WE HAVE A QUESTION FROM WILL
NATHAN. DO YOU SEE LONG TERM
TOXICITIES ASSOCIATED WITH
STREAM INHIBITION IN MICE?
>> NOT YET. WE HAVE JUST
GENERATED THE PHOSPHOMUTANT MICE
AND WE HAVE GENERATED PHLOX
MICE. SO THERE IS -- THERE ARE
SEVERAL MUTANTS OF SUBUNITS OF
DREAM. SOME OF THEM DOUBLE
MUTANT COMBINATIONS ARE
EMBRYONIC LETHAL BECAUSE THEY
ARE FUNCTIONING OTHER COMPLEXES
THAT ARE REQUIRED FOR PROMOTING
CELL CYCLE. THAT'S WHY WE
GENERATED NOW DREAM SPECIFIC
MOUSE MUTANTS, BECAUSE THAT
HASN'T BEEN ACCOMPLISHED YET. WE
ARE CURRENTLY INVESTIGATING
THEM. IN PARTICULAR WE ARE
INTERESTING IN HOW THIS ACTS IN
TERMINALLY DIFFERENTIATED CELL
TYPES SO THE FIRST CELL TYPE WE
LOOK AT NEURONS BECAUSE THEY
DON'T HAVE ANY OF THE
PROBLEMATIC OF CYCLING AND
WHETHER SOME SUB UNIT IS THEN
FOR INSTANCE POLYCOMPLEX THAT
DRIVES S PHASE SO THAT'S QUITE
SOME COMPLEXITY AREN'T THE
SUBUNITS THERE. BUT WE BELIEVE
WE CAN LEARN MUCH MORE NOW WITH
HAVING DREAM SPECIFIC MUTANTS
AND CELL TYPE SPECIFIC
ABROGATION OF DREAM IN PLACE.
>> PHILLIP ASKS WHY DON'T
FEMALES USE TMEJ ON THEIR OWN
DAMAGE?
>> SO THEY SEEM TO REALLY
PROTECT THEIR OWN GENOME SO WE
SEE IN FEMALES ALSO SOME
SENSITIVITY WHEN THEY ARE TMEJ
DEFICIENT, LIKE IN
HERMAPHRODITES BUT IN
(INAUDIBLE) THEY PREVENT TMEJ TO
ACT UPON THE MATERNAL GENOME SO
IT IS PROBABLY SOMETHING THAT
HAPPENS PRIOR TO THE FUSION OF
THE PATERNAL AND MATERNAL
NUCLEI. IT IS LIKELY THAT IT
OCCURS IN THE CYTOSOL SO WE
GENERATED STUDIES FOR TMEJ AND
WHERE IT ACT AND WHICH LOCATION
IT ACTS TO FIGURE THIS OUT
BETTER. THERE SEEMS TO BE REALLY
A SELECTIVE USAGE ON THE
PATERNAL GENOME BUT NOT THE
MATERNAL, AT LEAST NOT IN THE
ZYGOTE.
>> QUESTION, WHAT IS THE
EVOLUTIONARY ADVANTAGE TO HAVING
GAINED RELATED TO DNA REPAIR
SUPPRESSION IN HUMANS?
>> YES. SO THAT QUESTION I GET
ALL THE TIME. IF SOMETHING
WORSENED DNA WHY ON EARTH WOULD
YOU HAVE IT? I THINK THERE ARE A
COUPLE OF ANSWERS TO THAT. ONE
ANSWER IS THAT WHEN WE LOOK AT
LIN 52 MUTANTS OTHERWISE VERY
HEALTHY, WE DO SEE A SLIGHT
DECREASE. SO IT IS POSSIBLE
THERE IS A CERTAIN COST TO
IMPROVING SOMATIC REPAIR THAT
COULD THEN GO AT THE EXPENSE OF
THE GERM LINE. AND THIS WOULD
CERTAINLY PARTICULAR IN C
ELEGANS BE SELECTED AGAINST
IMMEDIATELY, SUCH A TRAIT
BECAUSE IT IS ALL ABOUT RAPID
REPRODUCTION. THAT MIGHT BE PART
OF THE ANSWER. THE OTHER ANSWER
COULD BE THAT IT MIGHT HAVE
CO-EVOLVED WITH CELL CYCLE
BECAUSE THE DREAM CONTROL CELL
CYCLE GENES. WE KNOW DREAM
ABROGATION ITSELF IS
INSUFFICIENT TO DRIVE CELLS INTO
CYCLING, ADDITIONAL STRONG
ONCOGENE FOR THAT. BUT IT
CONTROLS GENES BECAUSE UPON
ENTRY INTO S PHASE, MANY DNA
REPAIR MECHANISMS ARE INDUCED.
THAT ARE NOT PRESENT IN G1. THE
DREAM IS THE MECHANISM THAT
CONTROLS THIS INDUCTION OF
REPAIR GENE SO THERE COULD BE A
CO-EVOLUTION OF THE REQUIREMENT
OF S PHASE ENTRY AND THE
RESTRICTION AND THE ACTIVATION
OF DNA REPAIR GENES. SO THAT
COULD BE A SECOND ANSWER. THIRD
ANSWER COULD BE, IT IS JUST NOT
-- IT IS JUST NO REASON TO
MAINTAIN SOMATIC GENOMES, THERE
IS NO REASON NOT RESTRICTING IT.
BUT GIVEN THIS IS SO CONSERVED
THIS PHENOMENA FROM WORMS TO
HUMANS THERE IS -- THERE MUST BE
SELECTIVE ADVANTAGE OF CURBING
SOMATIC DNA REPAIR.
>> LOOKS LIKE (INAUDIBLE) HAS A
QUESTION.
>> WONDERFUL TALK. REALLY
ENJOYED IT. I UNDERSTAND
FUNCTIONING FOCUSING MOSTLY ON
AGING. SO YOU ARE DOING STUDIES
IN QUIESCENT CELLS. HAVE YOU
CONSIDERED USING DIVIDING CELLS?
OR GET MORE INFORMATION ABOUT
CANCER? SO WHEN WE TREAT
DIVIDING CELLS WITH HARMINE, WE
SEE NO BENEFIT BECAUSE IN
DIVIDING CELLS IN EVERY S PHASE
YOU GET ANY WAY THE DISASSEMBLY
OF THE DREAM COMPLEX. SO THIS
SEEM TO BE PREDOMINANTLY
BENEFICIAL FOR NON-DIVIDING
CELLS BUT IF YOU THINK ABOUT
STEM CELLS, MANY OF THE STEM
CELLS COMPARTMENTS ARE MOSTLY
QUIESCENT. THINK ABOUT
HEMATOPOIETIC STEM CELLS MOST
ALMOST ALL ENTIRE LIFE IN
QUIESCENT STATE, THEY HAVE
RESTRICTIONS IN REPAIR SO WHAT U
YOU FIND IN STEM CELL AGING ARE
NHEJ MEDIATED REPAIR FUSIONS.
THAT -- AND YOU FIND THAT WITH
AGING THOSE THAT ARE SELECTED
FOR ARE THEN FUSION ASSOCIATED
TO AGE DEPENDENT LEUKEMIA. SO WE
THINK THIS COULD BE VERY
BENEFICIAL IN THIS QUIESCENT
STEM CELLS TO PREVENT
ACCUMULATING GENOME ABERRATIONS
THAT DRIVE CANCER IN THE OLD
AGE. SO THIS COMES I THINK TO
QUITE EXTENT FROM DORMANT CELLS,
DORMANT CELLS WHICH HAVE ALL THE
REPLY KAYTIVE POTENTIAL OF STEM
CELL SO THERE WE THINK WHERE
THIS COULD HAVE HAVE VERY
IMPORTANT IMPLICATIONS.
>> THANK YOU.
>> DO YOU WANT TO CLOSE IT OUT?
LOOKS LIKE WE HAVE NO MORE
QUESTIONS IN THE CHAT.
>> WE ONLY HAVE ONE COMMENT FROM
THE VILHELM, THANK YOU FOR ALL
YOUR ANSWERS VERY STIMULATING. I
WOULD LIKE TO ADD THANK YOU FOR
DR. SCHUMACHER'S WONDERFUL TALK
AND REALLY APPRECIATE SHARING
THESE FINDINGS. THANK YOU SO
MUCH.
>> GOOD TO SEE YOU.
>> THANK YOU.
>> THANK YOU SO MUCH. IT WAS AN
HONOR.
>> THANK YOU. 1561 01:09:59,128 >> THANK YOU. TAKE CARE.