WELCOME EVERYBODY TO FIRSTLY A

OVERVIEW OF WHAT WE DO HERE AT

STONY BROOK RELATED TO DNA

DAMAGE AND REPAIR.

TOXICOLOGY.

AS YOU CAN SEE FROM THE NUMBER

OF VEINS HERE IT WOULDN'T HAVE

BEEN POSSIBLE IN A SHORT TIME TO

HAVE A SEPARATE PAGE FOR

EVERYBODY, SO I JUST PARAPHRASED

WHAT PEOPLE WORK ON AND THOSE OF

YOU WHO FEEL CHEATED IN THE WAY

I'VE DONE IT, PLEASE FORGIVE ME.

BUT IN ANY CASE, I DON'T HAVE TO

SAY ANYTHING ABOUT WHAT CARLOS

DE LOS SANTOS WORKS ON BECAUSE

HE'S OUR SPEAKER TODAY.

WE'LL FILL YOU IN A LOT BETTER

WAY THAN I COULD.

OUR COLLEAGUE DANIEL -- WORKS ON

DNA REPLICATION AND REPAIR

MECHANISMS IN MITOCHONDRIAL DNA

AND HIS LAB AND MY LAB HAD

COLLABORATED ON SOME STUDIES

RELATED TO THIS.

IN MY OWN LAB, WE'VE BEEN

INTERESTED FOR A LONG TIME IN

VARIOUS TYPES OF OXIDATED DNA

DAMAGE, PARTICULARLY HOW THIS IS

PROCESSED BY DECISION DNA REPAIR

PROTEIN.

SEMI SEPARATELY FROM THAT ALSO

FOR A LONG TIME QUITE A LOT OF

INTEREST IN CELLULAR RESPONSES

TO OXIDATIVE STRESS AND THE

INDUCIBLE DEFENSES THAT ARE

MEDIATED AS PART OF THAT.

AND I PUT AN ASTERISK BY MY NAME

NOT BECAUSE IT'S ANYTHING

SPECIAL BY ME EXCEPT THAT AS YOU

CAN SEE AT THE BOTTOM OF THIS

SLIDE, I WAS RECRUITED THROUGH

AN INTERDISCIPLINARY CONSORTIUM

HERE AT STIN STONY BROOK FOR

INTERDISCIPLINARY ENVIRONMENTAL

RESEARCH WHICH IS A MECHANISM TO

TRY AND MEDIATE ACROSS THE

CAMPUS IN ALL DIFFERENT

DEPARTMENTS STUDIES OF THE

ENVIRONMENT AND FOR MY OWN

RECRUITMENT AND THAT OF ME GEAL

GEAL -- MIGUEL GAWRS SAW O GARCIA ON THE

IMPACT OF HUMAN HEALTH.

MIGUEL IS SITTING HERE IN THE

ROOM HE STUDIES REPLICATION

FIDELITY.

FOR EXAMPLE WHEN HE WAS POST DOC

WITH TOM -- SOLVED THE STRUCTURE

OF DNA POLYMERASE SO HE'S A

PROTEIN STRUCTURAL BIOLOGIST AND

ALSO QUITE INTERESTED IN

PROTEINS THAT REGULATE THE GENE

EXPRESSION IN MITOCHONDRIA.

ARTHUR -- I THINK PRETTY MUCH

EVERYBODY IN THIS SYSTEM KNOWS

REASONABLY WELL ALREADY ARTHUR'S

BEEN WORKING FOR MANY YEARS ON

MUTAGENESIS AND MOLECULAR

CARCINOGENESIS AND IN RECENT

YEARS HAS REALLY BEEN AN

EMBLEMATIC STUDY OF A COMPOUND

CALLED -- ACID WHICH IS FOUND IN

SOME WEEDS AND CONTAMINATES

VARIOUS AGRICULTURAL PRODUCTS

AND THIS GIVES RISE TO SOMETHING

THAT INITIALLY WAS KNOWN AS --

TURNS OUT TO BE DUE TO A DNA

DAMAGING AGENT THAT'S PRODUCED

BY THESE AND HE AND HIS GROUP

AND COLLABORATORS HAVE

CHARACTERIZED THE TUMORS AND

NEXT ROW, NEPHROTIC ISSUE THAT

ARISE FROM EXPOSURE TO THIS

AGENT.

THEY'VE DONE THE STRUCTURE OF

THE LESIONS IN DNA AND HOW THEY

PROVOKE MUTAGENESIS AND HOW THEY

ARE REMADE.

AND AS A RESULT OF THEY ARE

INTERESTED IN THE STRUCTURAL

BIOLOGY OF THOSE LESIONS AND THE

REPAIR SYSTEM THAT PROCESS THIS.

MS. JONES AND CHARLES HAVE BEEN

LONG MAIN STAYS OF STUDIES --

EXCUSE ME --

>> LOOKS LIKE HE'S TRYING TO

PUSH CONTENT.

>> I'M NOT PUSHING ANYTHING.

>> LOOKS LIKE THERE MIGHT BE

DUAL NOTES.

>> I DON'T KNOW IF ANYONE ELSE

HEARD THAT BUT BRIEF

INTERRUPTION.

IN ANY CASE, FRANCIS JOHNSON AND

CHARLES HAVE LONG BEEN MAIN

STAYS OF GENETIC COX CALL AT

STONY BROOK.

CHARLES IS AN ORGANIC CHEMIST

STILL GOING STRONG AT NEARLY 82

YEARS OLD I THINK IT IS

EXAMINATIONS PRODUCES SPECIFIC

DEVELOPED SYNTHESIS METHODS TO

PRODUCE SPECIFIC DNA LATIONS.

SO THIS IS THE GUY THAT INVENTED

THE TETRO -- THAT'S SO WIDELY

USED AS A SUBSTITUTE FOR REGULAR

BASIC SITES IN HUGE VARIETY OF

STUDIES AND MANY LABORATORIES.

HIS COLLEAGUE CHARLES -- TWO OF

THEM ARE PHYSICALLY LOCATED IN

THE CHEMISTRY DEPARTMENT BUT

THEY ARE ALSO PART OF THE

DEPARTMENT OF PHARMACOLOGICAL

SCIENCES.

CHARLES IS INTERESTED IN THE

ANALYSIS OF MOLECULES THAT

CONTAIN DNA DAMAGE BY MASS SPECT

TOM TREE AND LIQUID

CHROMATOGRAPHY AND HE SEES TO IT

THAT THE NUCLEOTIDES ARE

PREPARED ARE OF THE HIGHEST

COLLEAGUE.

OUR COLLEAGUE ORLANDO WHO IS

PHYSICALLY WITH US AT THE

MOMENT, HE'S BEEN ON SABBATICAL

IN -- PAPERS ON DNA INTRASTRAND

CROSS LINKS AND THE SPECIFIC

MECHANISMS AND EFFECTS THAT THEY

PROVOKE.

THERE ARE SOME INDEPENDENTLY

FUNDED JUNIOR INVESTIGATORS WHO

ARE RESEARCH FACULTY HERE.

-- IS A CLOSE COLLEAGUE OF

ARTHUR.

SHE WORKS ON STUDIES RELATED

THAT TO -- ACID, THE MECHANISM

OF DNA DAMAGE AND THE PRODUCTION

OF RENAL DISEASE AS A RESULT OF

THAT AGENT.

MARK LOOKEN IS ASSOCIATED WITH

CARLOS DE LOS SANTOS AND CARLOS

WILL HAVE MORE TO SAY ABOUT WHAT

HE DOES BUT HE'S HEAVILY

INVOLVED IN MAKING AND ANALYZING

THESE DNA LESIONS.

-- HAS DONE A LOT OF NICE WORK

ON POLYMERASE AND IS CONTINUING

THAT WORK.

HE'S AN ASSOCIATE OF THE --

LABORATORY.

-- JUST JOINED US HERE FROM

BROOK HAVEN LABORATORY AND SHE

HAS A LOT OF EXPERIENCE IN

RADIATION BIOLOGY AND IS DOING

SOME STUDIES OF HEAVY IONS --

>> SOMEBODY HAS TO MUTE.

WE SEE YOU NOW, PLEASE MUTE.

WE ARE MOVING AHEAD WITH THIS

PRESENTATION.

>> THANK YOU.

 JOINED US HE WORKS ON RADIATION

BIOLOGY AND PARTICULARLY

EXPRESSION OF A1 PROTEIN AND

SHE'S DONE SOME VARIOUS STUDIES

ON THE SPECIFIC EFFECTS OF HEAVY

IONS WHICH ARE -- HYALIN YUR

ENERGY TRANSFER AGENTS THAT

PRODUCE HEAVILY CLUSTERED

LESIONS IN DNA.

THOMAS/I/IS YOIS YOIFS -- THAT'S REALLY A

NUTSHELL OF WHAT IS REALLY A

GOOD CRITICAL MASS OF PEOPLE

HERE WORKING AT STONY BROOK ON

ISSUES RELATED TO GENETIC

TOXICOLOGY AND DNA REPAIR.

AND NOW I'LL TURN IT OVER TO

CARLOS.

>> ALL RIGHT, THIS IS STEVEN

LLOYD.

WE'RE STILL GETTING THE FEED

ONLY OF YOU AND WE ARE HEARING

BRUCE BUT WE'RE NOT GETTING ANY

OF THE FEED FROM STONY BROOK.

I DON'T KNOW IF THERE COULD BE

SOMETHING THAT MIGHT BE AMISS.

>> OKAY.

WHY DON'T YOU CALL THE BRIDGE

PEOPLE.

THEY'RE HAVING A SIMILAR PROBLEM

IN MISTBERG.

CALL 301-345-1967.

>> STONY BROOK UNIVERSITY IS A

HUGE CAMPUS, YOU HAVE THESE

AERIAL VIEW OF IT WHERE THE

MEDICAL CAMPUS ON THE FOREGROUND

AND BEHIND HERE ALL THIS IS

STONY BROOK CAMPUS AND WE ARE

DIVIDED -- BUT STILL --

>> BE SURE TO MUTE, PLEASE.

>> LET ME CONTINUE --

THIS IS THE MEDICAL CAMPUS AND

CLOISECLOSE UP VIEW -- THE HUGE BLACK

BUILDINGS ARE THE -- THESE TWO

CHRISTMAS BOXES ARE THE CLINICAL

DEPARTMENT OF THE MEDICAL SCHOOL

AND THESE ARE LOCATED, THIS IS A

SMALL TOWER IS THE BASIC SCIENCE

TOWER WITH PHARMACOLOGY LOCATE

IN THE SEVENTH AND EIGHTH FLOOR

AND FOR THOSE OF YOU THAT ARE

VERY GOOD EYESIGHT I SEE CAN

BRUCE SITTING HERE ON THE EIGHTH

FLOOR PREPARING THE SLIDE AT HE

JUST SHOWED.

SO LET ME GET OVER WITH THE

ACKNOWLEDGMENT NOW SO NOBODY

GETS UPSET SNL UNLESS IT'S A LEAD OF

PEOPLE ON MY LAB AND TRYING TO

HIGHLIGHT THE NAMES OF TANYA --

MONICA ESPECIALLY TANYA WHO HAS

BEEN INSTRUMENT ON WHERE WE'RE

GOING TO BE TALKING TODAY.

AND HE WAS WITH ME AND NOW HE

HAS A MORE INDEPENDENT POSITION

AND ALSO HE HAS BEEN A KEY

PLAYER THAT WE ARE GOING TO SHOW

YOU.

SO LET ME GO DIRECTLY TO THE

ISSUE VERY VERY DNA SPHER OF

WHAT CELLS MEAN WOULD BE TO SAY

THAT -- THE RATE OF DNA DAMAGE

IS SMALL BUT SMALLER THAN THE

RATE -- WE HAVE TO TALK -- THE

FACT WE HAVE TO BE TALKING ABOUT

RATE IMPLIES AN ECONOMIC --

ANDOLOGY SO IMPLIES THAT YOU

CANNOT EVER AVOID DNA DAMAGE.

THE DNA DAMAGE IS HIGHER THAN

THE REPAIR RATE AND WHEN THE

BALANCE HAS A BOTTOM LINE, YOU

HAVE SEVERAL REPAIR DISEASE AND

NORMAL PROCESSES LIKE AGING OR A

TERRIBLE DISEASE LIKE CANCER

THAT SOMEONE SEES AS THE

ULTIMATE AGING MECHANISM.

SO WHAT ARE THE TYPE OF DAMAGES?

WELL PLENTY ALL OVER FROM

EXOGENOUS AND ENDOGENOUS SOURCES

AND FROM LARGE -- TO VERY VERY

SMALL PREACTIVE OXYGEN SPECIES.

ALL THAT ARE REALLY GOING TO

DAMAGE DNA CAN PRODUCE DOUBLE

STAND BREAK SINGLE STRAND BREAK,

SINGLE BASE DAMAGES -- CROSS

LINK AND A VERY SPECIFIC

REGULATION INDUCED DAMAGE THAT

ARE WHOLE CLUSTER LESIONS THAT

TOUCH IT ON ITSELF.

WHERE ARE THE REPAIR MECHANISMS,

FIVE MECHANISMS THESE APPLY JUST

FOR REPLICATION SO ACTUALLY FOUR

MECHANISMS THAT TRY TO CORRECT

DNA DAMAGE.

AND TODAY WE ARE GOING TO BE

FOCUSING ON SOME NUCLEOTIDE

REPAIR.

WHAT ARE THE GENERAL -- LET ME

POINT TO THESE.

WHAT ARE THE GENERAL LESIONS

THAT ARE SUBSTRATES.

WELL VERY VERY DIFFERENT

CHEMICAL -- FROM VERY LARGE

AROMATIC CARBONS -- AGENT, SOME

UV DAMAGE, THE FAMOUS CYCLO GLUE

TAIN -- AND ON THE RIGHT SIDE

THAT -- THAT CAN FROM ENDOGENOUS

OXIDATIVE LESIONS -- THAT COMES

FROM LIPIDS OXIDATION.

LET ME EMPHASIZE HERE THAT ARE

OFFICIALLY REPAIRED BY BASIC

LESION REPAIR AND THE NOOK LACE

CAN BE REPAIRED BY NUCLEOTIDE

EXCISION REPAIR.

HOW DOES IT WORK.

NUCLEOTIDE EXCISION REPAIR CAME

INTO BIG PRUDENTIAL, ONE -- BIG BRUNCH ONE

ASSOCIATED WITH TRANSCRIPTION

AND THE SIGNAL TO DO THE REPAIR

COMES FROM POLYMERASE TALKING.

AND I'M NOT GOING TO SAY

ANYTHING ABOUT THAT.

I'M GOING TO BE TALKING MOSTLY

ABOUT GENOMIC REPAIR.

THE IDEA IS THAT SOME SORT OF

SOME DAMAGE ON A BASE OR SUGAR

OR BREAK OF THIS DNA, WE PRODUCE

A HELIX DISTORTION AND THAT IS

ENOUGH FOR XPC -- 3B CONFLICTS

TO LOAD INTO THE LESION AND

INITIATE THE RESPONSE.

AND CAL CONCOMITANT WITH THE

HELIX -- CAUSES A DECREASE IN

THE STABL STABILITY OF THE DOUBLE

HELIX.

DNA OF NUCLEOTIDE ADHESION

REPAIR THAT I'M NOT GOING TO BE

TAUBING ABOUT.

WE ARE GOING TO BE FOCUSING

MOSTLY ON DNA STUDIES AND WHAT

ARE THE FACTORS THAT XTC --

DONATION.

FOUR YEARS AGO, FIVE YEARS AGO

THE GROUP OF MEMORIAL

SLOAN-KETTERING COME OUT WITH

THE STRUCTURE OF THE -- OF THE

XPC3B IN COMPLEX WITH THE --

CONTAINING DNA MOLECULE AND THEY

RARELY MAKE A IS HE VERY STRONG

CASE FOR THE MECHANISM THAT WE

SHOW BEFORE EXPLAINING WHY ANY

AND THE REASON IS THAT DOES NOT

CONTACT THE LESION DIRECTLY, THE

LESION IS EXPOSED AFTER THE

COMPLEX BINDING TO THE DAMAGED

DNA AND XPC HAS -- SOMEHOW

ACCOMMODATE THE DAMAGED DNA

BETWEEN THEM FLIPPING OUT TO

UNDAMAGED NUCLEOTIDES MAKING

CONTACT MOSTLY WITH THE

PHOSPHATE OF THE DNA.

ONCE AGAIN, THE FACT THAT THE

LESION IS EXPOSED TO THIS AND

EXPLAIN WHY DIFFERENT STRUCTURES

CAN BE NICELY RECOGNIZED BY

GENOMICS REPAIR.

SO OUR TAKE ON THIS WAS

DIFFERENT WAS TO SAY WHAT CAN WE

LEARN FROM DNA LESIONS THAT ARE

TO GLOBAL GENOMIC REPAIR.

I'M GOING TO BE TALKING TODAY

ABOUT TWO STORIES.

ONE ABOUT DNA LESION -- AMINO

GROUP THAT ACTUALLY RESIST ANY

RECOGNITION, AND THE OTHER

FORM -- ON THE N6 AMINO GROUP OF

THE OXY AWE DEAN SEEN.

LET ME GO TO THE STORY OF -- WAS

ACTUALLY DISCOVERED OR WAS A USE

FOR THE RESEARCH FIELD IN DNA

REPAIR -- FOR MORE THAN 50

YEARS.

THIS IS THE TWO AMINO FLUORINE

INITIALLY A COMMERCIAL PRODUCT

USED AS AN INSECTICIDE ON THE

COUNTRY HERE IN THE UNITED

STATES.

AND THE TWO FLUORINE ACTUALLY

ENVIRONMENTAL COMPOUND THAT

STILL IS IN THE ENVIRONMENT ARE

FORTUNATELY VERY VERY LOW

CONCENTRATIONS.

WHAT HAPPENED WITH THIS

COMPOUNDS, THE ENVIRONMENTAL ONE

GETS REDUCED TO THE -- AMINO

GROUP OF THE TWO AMINO FLUORINE

GETS OX DIESED TO THE SAME

INTERMEDIATE THAT UPON FURTHER

OXIDATION CAN REALLY PRODUCE

ULTIMATE CARCINO GENERA CARCINOGEN THAT

RESECRETARIES WITH DNA -- HAVE

VERY VERY CLEAR BIOLOGICAL

IMPLICATIONS.

TWO TYPES OF -- AT THE CA

POSITION AND THEY MAY BE -- AT

THE AMINO GROUP OR NOT -- AND

THOSE ARE THE FAMOUS AF --

AAFDGR.

WE KNEW A LOT ABOUT THESE AND

THOSE HAVE BEEN USED TO EXPLAIN

MOST OF THE CARCINOGENIC

PROPERTIES AND BIOLOGICAL

COMPLEX OF MYSELF FOR TUSKITY.

BUT THEY ALSO FORM A SMALL

PRODUCT THAT IS AN ADULT AT THE

AMINO GROUP OF PUTTING THE OX

AWE DEAN SEEN STILL IN TACT NOT

ATTACHED TO THE BASE AND IN THIS

CASE U.S.-RUSSIA AS  -- ONE IS MULTIGENIC 
IN

BACTERIA HAS BEEN SUGGESTED FROM

IN VITRO THAT IS ALSO -- AND IN

VIVO STORIES HAVE CONFIRMED

THAT.

THESE LESIONS STILL NEED FULL

INVESTIGATION.

BUT WE ARE INTERESTED IN THIS

LESION BECAUSE WE CAME ACROSS TO

A REPORT THAT SHOWS THAT THIS

MINOR PRODUCT OF AAS IS DNA

LESION.

AND IN THIS CASE, THESE TWO,

THIS IS THE, THESE TWO ARE THE

DG -- PERSISTS FOR MORE THAN TEN

MONTHS -- AFTER ADMINISTRATION

OF NITRO FLUORINE.

AFTER 10 MONTHS THE RAT WAS NOT

ABLE -- ADULTS.

LET ME SHOW YOU WHAT WE DO HERE.

WE DETERMINE FRACTURE OF DAMAGE

DNA AND DECIDE STEPS THAT WE CAN

SEE TO HAVE A GOOD DIDN'T NMENTD

AMOUNTED SAMPLE FOR

MARKETIZATION TO DO THE

ANALYTICAL WORK OF GETTING

CONSTRAINT FOR MOLECULAR

DYNAMICS SIMULATIONS THAT WILL

SATISFY THE NMR CONSTRAINT AND

CHARACTERISTIC OF THE NMR

SPECTRUM.

AND AT THE END TO REALLY

VALIDATE -- IF WE SOLVE HERE WE

COME BACK AND REITERATE A MORAL

DOSE.

AND THIS IS THE TYPE OF -- THAT

WE USE THAT ARE CALLED NOE

EXPERIMENTS AND WITH THAT, WE

CAN MAKE A LOT OF SENSE HOW THE

DNA IS.

WE DID IT IN -- SOLVENT AND THIS

IS ON THE -- CONTAINING HERE AT

POSITION C THE AAF -- AND THIS

SORT OF NOE WORK AS WE CALL IT

TELLS YOU THAT THE BASIS ARE

PRETTY WELL START AND WE DON'T

SEE ANY MAJOR PERTURBATION.

WE DO THE SIMILAR EXPERIMENT IN

H2O BUT IN THIS CASE WE FOCUS ON

THE EXCHANGE OF THE AMINO

PROTEIN BECAUSE WE CAN EASILY

IDENTIFY WHICH ARE FORMED AND

WHAT SORT OF ALIGNMENT THEY HAVE

OR -- ONLY THEY ARE NOT FORMED

ONCE AGAIN IN THE CASE OF THE --

THAT WE ARE STUDYING HERE --

WERE OBSERVED.

WHEN WE DID THE REFINEMENT AND

FOR THOSE OF YOU THAT MAY BE

ABLE TO CLOSE YOUR EYES -- THIS

IS WHAT WE OBTAINED WHERE THE

ADULT HERE AT THE AAF IS SHOWN

IN GREEN IS LOCATED IN THE MINOR

GROUP OF THE DNA AND THAT'S NOT

THE HELIX ALMOST AT ANY

POSITION.

AND LOOKING AT DIFFERENT VIEWS

OF THAT HERE IS FROM THE MAJOR

GROUP YOU DON'T SEE ANY TRACE OF

THE LESION FROM HERE ON THE

CENTER OF THE DUPLEX.

THAT'S NOT LEAVE ANY OPENING

THAT YOU CAN SEE THROUGH 90

DEGREES.

THAT'S THE MINOR GROUP OF THE

DNA.

THIS IS THE MAJOR GROUP THAT IS

DONE HOW SHALLOWER THAT YOU WILL

NORMALLY SEE AND HERE IN GREEN

YOU CAN START SEEING PART OF THE

GROUP OF THE ADULT.

THIS IS A MINOR GROUP VIEW OF

THE AAF -- VERY VERY WELL PASSED

AGAINST THE TWO STRANDS OF THE

DNA AND I KNOW THAT IT DID

RETURN TO SEE HOW IT LOOKS LIKE.

THOSE ARE THE START OF THE MAIN

PERTURBATIONS THAT YOU CAN

OBTAIN AT THE LESION SIDE IS

THAT THE WITNESSED OF THE MINOR

GROUP GETS REDUCED, 5.9 IS THE

NORMAL WITNESSED, DIFFERENT

SIMULATIONS BETWEEN 2 AND 4.7,

DIFFERENT PLACES.

THAT THAT OF THE MINOR GROUP

ALSO GOES INCREASES FROM THE

NORMAL 4.6 TO 5.6 TO 7.2.

THAT'S WHY I SHOW THE MAJOR

GROUP LOOKS SO SHALLOW.

AND THEN THEY ARE CHANGING THE

DAMAGED SIDE -- AND WE MAKE SURE

THE EXPOSED SURFACE OF THE ADULT

AND REALLY IS ONLY 7 PEOPLE AND

THAT CORRESPONDS TO THE EDGE OF

THE ADULT WHERE WE HAVE THE --

DIRECTLY LOOKING AT IT.

ANOTHER POSSIBILITY THAT YOU

HAVE DURING ANY MATH IS NOT ONLY

ARE YOU SEEING THE SOLUTION

STRUCTURE AND YOU CAN OBSERVE

DYNAMIC BEHAVIOR BUT ALSO YOU

CAN SEE INDIVIDUALS HOW STABLE

THEY ARE.

AND THE WAY THAT USES THAT, YOU

LOOK AT THE AMINO -- YOU STUDY

THE TEMPERATURE AND YOU SEE

WHICH ONE DISAPPEARED FIRST AND

WHICH ORDER THEY DISAPPEARED.

AND THE EXPERIMENT IS THAT WHEN

THE BASE ARE OPEN, IT'S EXPOSED

TO THE SOLVEN SOLVENT IT CHANGES WITH

WATER AND YOU LOSE THE ANIMAL

SIGNAL.

THE MESSAGE OF THIS EXPERIENCE

IS THAT HIGH TEMPERATURE STILL

YOU ARE SEEING THAT THE ONLY

BASE OR ONLY TRACE OF BAY

FORMATION IS LOCATED AT THE

DAMAGED SITE.

THIS BELONGS TO THE ADOPTED

WARNING.

AND THIS IS QUITE UNUSUAL

BECAUSE NORMALLY WHAT YOU SEE ON

DAMAGE DNA IS WHEN YOU DO THIS

SORT OF ANIMAL MELTING, THE

DUPLEX MELTS FROM THE END TOWARD

THE CENTER WHERE THE LESION IS

AND AT THE SAME TIME FROM THE

LESION TOWARDS THE END AND THE

REASON OF THAT IS BECAUSE DNA

LESIONS DISRUPTED DIMINISH THE

STABILITY OF THE -- HERE WAS

COMPLETELY DIFFERENT.

AND WE CONFIRMED THAT BECAUSE WE

WENT AHEAD AND USED MELTING

PROFILE AND FORMAL ANALYSIS WE

COME OUT THAT THE AAF MODIFIED

DUPLEX WAS MORE STABLE, MORE

STABLE THAT THE CONTROL GROUP

WITH THE -- SEQUENCE AND THE

DELTA G OF DUPLEX FORMATION WAS

LOWER AND THE DELTA DELTA G THAT

YOU CAN SEE HERE IS ABOUT 2.6 --

THAT MEANS THIS LESION ACTUALLY

SEPARATE THE DUPLEX STRUCTURE

INSTEAD OF STABILIZING IT.

SO THE CONCLUSIONS THAT WE DRAW

FROM HERE WAS THAT THESE DUPLEX

IS A REGULAR HELIX BELONGS FROM

THE FAMILY WITH -- ALL

THROUGHOUT.

THE LESION INCREASES THE DUPLEX

TURNALTERMINALS STUDY, THE AAF DECIDES

ON THE MINOR GROUP WITHOUT

RECRUITING OUT OF THE HELIX

BOUNDARIES AND FOR THAT, THE

MINOR GROUP IS HOW SHIFTING THE

AAF FROM WATER EXPOSURE.

THEN WITH THE HELP OF ORLANDO

LABORATORY ON ONE OF HIS

STUDENTS, WE TRIED TO SEE WHAT

HAPPENED WITH THAT INCISION, THE

IN VITRO INCISION OF THOSE

LESIONS.

AND WE ARE PROUD, VERY PROUD OF

THIS -- BECAUSE THIS IS REALLY

NOT THE WORK THAT WE NORMALLY DO

BUT I GUESS THE MESSAGE HERE IS

QUITE CLEAR.

LINE TWO IS ONE THREE BUT IT'S A

WELL-KNOWN SUBSTRATE FOR ANY --

AND YOU CAN SEE THE DIFFERENT

PRODUCTS THAT HAVE FORMED.

WHILE THREE, FOUR AND FIVE ARE

THREE DIFFERENT HELIX CELLS A

WHOLE SELECTION PREPARATION IN

NONE OF THEM WE CAN SEE THE SAME

PRODUCTS FORMED.

THAT MEANS THE PLASMID

CONTAINING A SINGLE DG INTO

AA -- HAS NOT BEEN INSIDE.

SO HOW THIS RESULT PUTS US ON

THE GENERAL SCHEME, HOW ANY

WRECKER ANYTHINRECOGNITION WORKS.

WELL IT MAKES ENTIRE SENSE AND

REALLY SUPPORT THIS SCHEME

BECAUSE THE LESION IS NOT

PERTURBING, THERE'S NO DNA

BENDING, GENERALLY ONE OF THE

PREFERRED IN BULK PERTURBATION

FOR ANY RECOGNITION AND THERE'S

NO STABILIZATION OF THE DNA

DUPLEX.

SO EXPLAIN FREELY VERY NICELY

WHY XPC 3D KIND OF LOAD INTO THE

DNA LESION.

ORBIT THINKING ABOUT THE

STRUCTURE BUT WHAT THIS TELLING

US THAT IS THE -- HOW TO OPEN

THE HELIX AND ACCOMMODATE THE

UNDAMAGED RES RESIDUE TO PUT IN

CONTACT WITH THE PROTEIN CELL TO

SEPARATE THE TWO STRANDS OF THE

DNA.

SO FROM HERE THEN WE SAY

OKAY-THIS IS WHAT THE HYPOTHESES

THAT WE SAW AT THAT TIME AND WE

PROPOSED TO THE NIH ACTUALLY TO

THE NIHS TO STUDY THIS

HYPOTHESES.

AND THAT IS THAT SOME HAVE

THE -- THAT WILL CAUSE STRUCTURE

PRESERVATION AND CAUSE -- AS A

RESULT OF THAT, THEY WILLOW BAY

GLOBAL GENOMIC -- CELLULAR DNA

AND ARE LIKELY TO HAVE A

PREVALENT ROLE IN CHEMICAL MUTE

GENESIS AND DISEASE.

AND TO IDENTIFY THAT, LET ME

COMPARE THIS, THE AAF STRUCTURE

HERE WITH THE STRUCTURE OF --

INTO DG, AND I HAVE BEEN

INVOLVED WITH THIS WORK IN --

WHAT YOU CAN SEE HERE THAT THE

MAIN DIFFERENCE IS THAT THE

POSSIBILITY OF PARKING THE TWO

STRANDS AGAINST THE -- IN THAT

SENSE ONE PHASE OF THE -- IS

EXPOSED TO WATER.

AND THERE IS MUCH LESS

COMPACTION HERE.

CLEARLY HERE THERE IS NO WATER

MOLECULE GETTING IN CONTACT WITH

THE AAF MOLECULE.

OOPS.

WELL, SORRY I'M LOOKING LIKE

THAT BUT WHAT THIS TRANSPARENCY

THAT I SHOULD SAY, LET ME FIND

AN AAF -- GIVE ME A SECOND.

WHAT I WAS SHOWING THERE IS THAT

ONE CHARACTERISTIC OF THIS AAF

ADULT IS FIRST THAT THIS

CARBON -- IS AN SPA2

HYBRIDIZATION.

THIS THAT MEANS THIS IS ON THE

SAME PLANE AND THIS RANGE IS NOT

LIKE IT IS IN THE CASE OF -- IN

ADDITION TO THAT WE HYPOTHESIZE

THAT FROM THE -- FOLLOW THE

CURVATURE OF THE DNA HELIX SO IT

KIND OF ACCOMMODATES AND IMPACTS

MUCH BETTER THAN THE DNA

STRUCTURE.

SO BACK TO THE PLACE WHERE I

LOST MY SLIDE.

I IDENTIFIED ANOTHER LESION --

COMPOUND OF IMPORTANCE THAT IS

CALLED -- THAT SOMEHOW WILL BE

ABLE TO MUCH WHAT WE SAW WAS

GOING TO BE THE TOPOLOGY NEEDED

FOR THIS ADULT TO BE RESISTENT.

IN THE SENSE THAT THIS LESION --

BY AAF AND THE BAY LESION

SLIGHTLY DIFFERENT BUT STILL A

LEAGUE THAT FOLLOWS THE

CURVATURE OF THE HELIX.

REGARDING -- IS PRESENT IN --

THIS ENGINE AND PARTICULAR

MATTER IN THE AIR.

IT'S A STRONG MAMMALIAN MUTAGEN

AND IT'S ALSO A IS HE VERY

STRONG BACTERIAL MUTAGEN --

INDUCES MITRAL NEW CALCULATED -- NOOK LAID

HAS BEEN ATTRIBUTED TO LUNG

CANCER IN HUMANS MAINLY IN COAL

PATIENCE IN ENGLAND INITIALLY

AND ABOUT A COUPLE OF WEEKS AGO

THE NIAHS ISSUED A COUPLE

REPORTS OF THE IMMUNLOGICAL LINK

OF LUNG CANCER IN COAL MINORS

WORK HERE IN THE UNITED STATES.

IT'S A GOOD CANDIDATE TO BE

RESPONSIBLE ARE FOR THAT.

WE KNOW MORE ABOUT THE

ACTIVATION.

THIS SORT OF ACTIVATION WAS

AGAIN IMPLIED REDUCTION OF THE

NITRO GROUP TO -- A COMPOUND BUT

IT'S FOR THE ACTIVATION BY

PHOSPHORYLATION -- AND FORMS --

DERIVATIVE AND CREATES A

POSITIVE CHARGE THAT CAN APPEAR

IN THE NITROGEN OR CAN APPEAR

HERE IN THIS CARBON ACTUALLY IS

THE LOOK ALIKE.

IN THIS CASE LIKE AT AAFK CAN

REACT TO FORMS -- OR ADULTS ON

THE PERIPHERAL AMINO GROUP.

ONE IN THIS CASE THE ONE THAT WE

ARE GOING TO SHOW RIGHT NOW ARE

ALSO IN THE CASE OF THE OX OH

ADENOSINE CAN BE IDENTIFIED.

BUT DIFFERENT THE AAF WAS A LOT

OF WORK ON THAT, WE HAVE TO

START IN THIS CASE MUCH EARLIER

PREPARING THIS AND THAT HAS BEEN

THE GROUP THAT WERE MOSTLY OF

NOT LOOKING WHERE HE

INCORPORATED INTO THE DNA AND WE

HAVE CREATED ENOUGH MATERIALS OF

THE ADULT TO BE STUDIED.

AND WE INTRODUCE IN THIS CASE IN

A SELF COMPLEMENTARY DUPLEX HERE

AT POSITION FIVE AND WE

DETERMINED THE ANIMAL -- GOING

TO SHOW ALL THE DETAILS EXACTLY

BY THE SAME WAY THAT WE DID

BEFORE.

IN THIS CASE, ONCE AGAIN THE

PROTEIN IN THIS MINOR GROUP

THAT'S NOT REALLY THE DUPLEX

STRUCTURE AND IS PROTECTED

ALTHOUGH THE PARKING HERE THAT

WE SEE ON THE ADULT MAY NOT BE

AS STRONG AS THE ONE THAT WE

HAVE SEEN IN THE CASE OF THE

AAF.

WHAT IS IMPORTANT FROM OUR

PERSPECTIVE BY NOW IS THAT THE

DUPLEX IS ALSO A HELIX

STABILIZING LESION AND ITS

LESION CAUSE AN STABILIZATION OF

THE DNA DUPLEX OF ABOUT 1.5

KILO -- UNFORTUNATELY WE DON'T

HAVE THE AGAIN, I LOST THIS.

WE DON'T HAVE THE TRANSPARENCY

SHOWING THE NAR REPAIR --

BECAUSE WE ARE PREPARING THE

PLASMA TO PERFORM THAT RESULT.

BUT WE ARE QUITE CONFIDENT THAT

THE CHANCES IT WILL BE A SIMILAR

RESULT THAN AAF WILL BE PRESENT.

THERE ARE SOME REPORTS

INDEPENDENT OF OUR WORK SAYING

THAT AMINO -- REMAINS IN LIVER

OF RATS FOR TWO MONTHS IN

DELIVERANCE -- OF THE ANIMAL.

SO THIS AGAIN STILL GOES QUITE

WELL WITH THE MOBILE BECAUSE

WHATEVER IS HERE THAT DO NOT

CAUSE PERTURBATION WERE ENOUGH

TO PRODUCE THE STABILIZATION OF

THE HELIX IS GOING TO BE SUPER,

IS GOING TO BE RESISTENT TO ANY

RECOGNITION.

AND IN OUR POINT OF VIEW, ANY

STRUCTURE THAT IS ABLE TO HAVE

THE CURVATURE THAT FOLLOWED THE

DNA AND IS ALSO GOING TO BE

ATTACHED BY SP SQUARE

HYBRIDIZATION TO THE DA -- OR

IT'S GOING TO BE TO BE A

CANDIDATE TO STABILIZE THE

HELIX.

FORTUNATELY EVEN THOUGH WE LOOK,

WE COULD NOT FIND MANY MORE

ENVIRONMENTAL TAL TOXINS THAT MEET

THIS TOPOLOGY.

SO EVEN THOUGH YOU CAN PREPARE

MORE OF THESE CHEMICALLY, THE

RELEVANCE FOR HUMAN HEALTH I

GUESS IS SO FAR IS GOING TO BE

UNKNOWN AND ONLY THESE TWO GUYS

ARE GOING TO BE OF CERTAIN --

SO LET ME NOW SWITCH GEARS

RAPIDLY TO -- THAT THIS IS THE

WORK THAT WE HAVE DONE IN

COLLABORATION WITH -- THIS IS

THE NATURAL PRODUCT, THAT IS THE

PLANT AND THAT GROUP PREFERRED

BRIEFLY IS A VERY VERY IMPORTANT

TOXIN, IT CAUSES THE NEPHRO

TOXICITY -- ALSO BOTH AA1, AA

STANDS FOR -- ONE AND TWO, THOSE

DID HDEFER ON DIFFERENT MODIFICATIONS

BUT BOTH OF THEM ARE GENO TOXIC

CAUSING -- AND WE KNOW THAT

AA -- FOR SEVERAL YEARS AND THAT

IS KNOWN BECAUSE PEOPLE WHO

ACCIDENT HERE TOOK LARGE

QUANTITIES OF -- HAS BEEN

RECOVERED AND THOSE THEURMS WERE

WERE -- TUMORS ITSELF WERE

ANALYZED AND HAS BEEN IDENTIFIED

AS A METHOD.

WELL NATIONAL TOXICOLOGY PROGRAM

IS ALREADY AN ESTABLISHED HUMAN

CARCINOGEN.

SO THE ACTIVATION OF THIS GUY ON

THE ACTION OF THE NITRO GROUP

BUT IN THIS CASE IMMEDIATELY

CLOSES TO -- THAT AFTER FURTHER

ACTIVATION BY --

PHOSPHORYLATION -- THAT IN THIS

CASE ONLY REACT AT THIS

POSITION -- WITH THE PERIPHERAL

AMINO GROUPS OF DG OR DA.

THE GROUP JOINS THEM INTRODUCED

THESE ON THIS METHOD NOT ONLY

THE PRODUCTION BUT ALSO HAVE TO

PUT IT ON THE DNA.

AND WE TOOK ADVANTAGE OF THAT TO

PREPARE LARGE AMOUNTS OF A

DUPLICATE WE NEEDED IN THE

LESION HERE IN THAT POSITION

SIX.

WE IDENTIFIED THE PRESENCE OF

THE ADULT WAS UNIQUE AND THE

OTHER SINGLE FORMATION.

THE TYPE OF EXPERIMENT THAT WE

DO SHOWED THAT THE STRUCTURE WAS

QUITE REGULAR, ALTHOUGH THEY

WERE WORSE THAN CHEMICAL -- I'M

NOT GOING TO GO INTO THAT BUT WE

ARE ABOUT T17 AND T17 WAS THE

TIMING TO THE ADULT LESION.

THE YE NOCI EXPERIMENT IN WATER --

THROUGHOUT THE DUPLEX WITH THE

EXCEPTION OF THE LESION

CONTAINING -- AND THIS SIGNAL

HERE WOULD TRACE IT TO BE --

PROTON OF THE ADULT.

PROTON OF THE ATOM.

THIS IS HOW WE SHOWED THAT, HOW

WE RULE OUT AND THIS IS THE

SIGNAL THAT APPEARED CLOSE TO

THE AMINO PROTON.

WE DID A LOT OF WORK WITH THAT.

WE WANTED NOT TO MAKE ANY

MISTAKE, WE DID NOT HAVE A LOT

OF INFORMATION REGARDING THE

LESION PARTNER T17 SO WE WENT

BACKWARDS AND WE PREPARED JUST A

NORMAL TIMING WHEN HE

SELECTIVELY -- ONE OF THE H5

PRIME PROTONS.

SO WE WERE ABLE TO SIMPLIFY

THE -- FOR ONLY ONE AND OBTAIN

REALLY A THROW OF NOE DATA FOR

THIS SINGLE MODIFICATION THAT

REALLY WAS ABLE TO LOCK T17 IN

POSITION.

THIS IS A STRUCTURE OF THE

ADULT.

NOW WE ARE LOOKING HERE FROM THE

MAJOR GROUP SIDE OF THE DUPLEX

WITH T17 IS COMPLETELY EXCLUDED

FROM THE HELIX UP HERE AT THE

MAJOR GROUP AND IS THERE JUST

TRYING TO PERHAPS SHOW SOME

HYDROPHOBIC INTERACTION WITH THE

ADULT ITSELF BUT NOTHING ELSE.

IT HAS NO ELECTROSTATIC WITH ANY

OTHER RESIDUE OF THE DUPLEX.

THERE IS THE -- INSIDE OF THE

DUPLEX AND VERY WELL STARTED

BETWEEN THIS -- G16 AND THIS IS

A TOP VIEW SHOWING THE

HYDROPHOBIC OR THE STUCK

INTERACTION THAT YOU NORMALLY

SEE ON THE HELIX ON A LESION

CONTAINING THEY SPARE ONCE AGAIN

T17 HERE COMPLETELY OUT OF THE

PICTURE AND THE HELICAL STAT AND

THOSE C5G18 AND C7 AND G16 AND

THE INTERACTION HERE IS GOOD.

WE DID ALSO THE THERMAL DYNAMIC

STUDIES ON THAT AND FOR OUR

SURPRISE BASED ON THE STRUCTURE

THAT IS A LESION ACTUALLY THEY

STABILIZED THE DUPLEX.

NOT BY MUCH BUT ON THE SEQUENCE

WE STARTED IT DOES IT BY 2.5

KILO CALORIE MOLE AND TWO

ADDITIONAL SEQUENCES THAT WE

STARTED AND THE REASON FOR THESE

TWO IS THAT THEY HAVE BEEN

IDENTIFIED TO BE HOT SPOT FOR

MUTATION ON P53 GENE AND WE

WANTED TO KNOW IF THERE WAS

SOMETHING SPECIAL ABOUT THAT

ALSO IS STABILIZING.

SO THE IDEA THAT PERHAPS WAS THE

LESION THAT WAS GOING TO

STABILIZE THE DUPLEX AND AVOID

ANY RECOGNITION REALLY IS NOT

SUPPORTED BY OUR -- STUDIES.

IN SIMPLE SUMMARY OF WHAT WE SEE

STRUCTURALLY ON THE LATIONS

ROOTS THE STABILITY OF THE

DUPLEX.

THE STRUCTURE IS PUBLIS PUBLISH TURNED

AT THE -- PERTURBEDLY LESION

SIDE -- AND INSPITE OF THIS

CHANGES THE DUPLEX RARELY SHOWS

THE FORMATION BUT IS STABILIZE

BY HYDROPHOBIC INTERACTION.

SO THIS CREATES NOW A PROBLEM

WITH THIS -- BECAUSE WE ARE

SEEING NOW A LESION -- DUPLEX

STRUCTURE AND REDUCES THE

STABILITY AND WE WANTED TO SEE

OKAY, GOOD XPC A CHART 23B LOAD

INTO THIS SORT OF PERTURBATION.

AND AT THE SAME TIME THAT WE

PUBLISH RESULTS IN NE NOOK LLOYD

RESEARCH HAS BEEN STUDIED THE

GLOBAL RECOGNITION AND IN

GENERAL RECOGNITION OF -- ACID.

AND THE MESSAGE WAS THAT THE

AVID WILL GO UP WHEN YOU ARE

DEALING WITH CELLS THAT ARE

DEFICIENT IN GLOBAL JEANNIEIC

REPAIR.

WHEN YOU ARE TALKING ABOUT XPC

CELLS THAT LACK GENOMIC REPAIR,

THE OTHER -- ARE LOWER.

THEY ARE RESISTENT TO THE

RECOGNITION AND INCISIONS OF NAR

AND BINDING ASSAY SHOW THAT THE

NAR THAT XPC3B CANNOT BIND TO

DNA CONTAINING THE HISTOLOGIC.

SO LET ME CONCLUDE HERE WITH A

COUPLE OF TWO POINTS THAT I WANT

TO MAKE REGARDING THAT FIRST

MORE OF THE ISSUE ARE NOT --

FIRST IDEA IS THAT THE

RECOGNITION -- BY GLOBAL GENOMIC

REPAIR SEEMS LESS EFFICIENT THAN

INITIALLY THOUGHT BECAUSE WE ARE

FINDING MORE STRUCTURAL MOTIF

THAT ARE ABLE TO ESCAPE LOWER

GENOMIC NER REPAIR AND THAT

EMPHASIZE BECAUSE THOSE LESIONS

WILL BE RECOGNIZED BY TCR.

SO THE CARBON THAT WAS REALLY

RECOGNIZED ALL THESE.

WE ALSO IDENTIFIED THE TOPOLOGY

OF DUPLICATE -- LESIONS AND

WHATEVER YOU CAN SEE AN AROMATIC

MAYITY THAT CONFORM INTO ADULTS

AND HAVE A CURVATURE NEXT TO --

REGION THEN SUSPICIOUS THAT THE

LATION IS GONE.

THAT LATION I LARYTION IS LATION LESION AN
D THEN GOING BACK

TO THE MECHANISM RECOGNIZES THE

LESION, WE CAN DO TWO THINGS.

WE CAN INVOKE OF DUPLEX

INSTABILITY, THERE SHOULD BE A

STABILITY THRESHOLD.

BEYOND THAT THE LESIONS ARE

GOING TO BE PREPARED BY A

RECOGNIZED BY XPC.

THE PROBLEM WITH THAT IS THAT

THE STABILITY THRESHOLD YOU WILL

HAVE WITH THE SIMILAR DUPLEX

THERMAL DYNAMIC EFFECT SOME

LESIONS THAT ARE GOING TO BE

RECOGNIZED AND SOME LESIONS ARE

NOT GOING TO BE RECOGNIZED.

SO WE SORT OF FAVOR MORE THAT

THE PRESENCE OF OTHER FACTORS

THAT NORMALLY ARE NOT EVIDENCE

BECAUSE WHEN THE LESION REALLY

STABILIZES THE DUPLEX IN LARGE

EXTENT, THESE ARE NOT IMPORTANT

BUT WHEN THE STABILIZATION IS IN

BETWEEN AND IS NOT SUFFICIENT OR

THAT'S NOT SUFFICIENTLY SEPARATE

THE DNA, THESE NARCOTICS CAN

MAKE A DIFFERENCE -- FACTORS CAN

MAKE A DIFFERENCE.

THOSE FACTORS THE ONES WE ARE

REALLY INTERESTED IS THE -- OF

THE AROMATIC MOIETY ESPECIALLY

IN THE FACT OF THE STRUCTURE

THAT -- HAVE SHOWN, HAVE

PUBLISHED THE DAMAGE IS

COMPLETELY EXPOSED TO THIS

ORDER.

SO THE HIGHER THE -- OF THE

ADULT, THE MORE DIFFICULT IT'S

GOING TO BE FOR THE SYSTEM TO

REALLY REACH THAT VERY HIGH

STRUCTURE.

SO LET ME FINISH HERE AND I WILL

BE GLAD TO ANSWER QUESTIONS IF I

CAN.

THANK YOU.

[APPLAUSE]

>> THANK YOU.

YOU CAN TURN ON THE LIGHTS IN

STONY BROOK SO WE CAN SEE YOU

AND THEN WE'LL GO AROUND AND ASK

ONE QUESTION AT A SITE IN THE

INTEREST OF TIME.

LET'S GO TO BALTIMORE.

ARE YOU THERE?

ARE YOU THERE, WILL?

UNMUTE.

OKAY.

LET'S MOVE ON.

W450EU8 I HAVWHILE I HAVE YOU, I HAVE A HE

REQUEST.

YOU'VE BEEN FOCUSING ON DID THE

NA THE MOST COMMON ONE IS THE --

AND ONE OF THE PECULIAR FEATURES

OF THAT IS THE REPAIR OF THE SIX

FOUR PHOTO PRODUCT IS VERY

EFFICIENT IN THE MAMMALIAN CELLS

BY SIX TO 12 HOURS THEY'RE ALL

GONE.

HOWEVER, THE CPD'S PERSIST EVEN

AT 24 HOURS.

DO YOU HAVE AN EXPLANATION FOR

THAT.

THEY SEEM TO BE EVADING THE

NUCLEOTIDIC REPAIR, THE GLOBAL

GENOME REPAIR.

ARE THEY IN A DIFFERENT LOCATION

OR DIFFERENT CONFIRMATION?

>> WELL, THE STRUCTURE OF THE

CPD BINDING DIMER IS NOT A DNA

STRUCTURE.

THE ALIGNMENT REMAINS AND THE

ENERGETIC PANELS IS REALLY LOW.

THAT'S NOT THE STABILIZED LESION

TO A VERY LARGE EXTENT.

IN ADDITION TO THAT, I WOULD

LIKE TO POINT OUT THAT IT DOES

NOT HAVE ANY -- GROUP HANGING

ANYWHERE FROM THE -- SO IT

CERTAINLY CAN BE WITHIN THE

GENERAL XPC RECOGNITION MOTIVE

THAT IMPLIES THERMAL

STABILIZATION ENOUGH TO SEPARATE

IT TO SPHRANLDZ O STRANDS OF THE DUPLEX.

AT THE SAME TIME, THE NUCLEOTIDE

RECESSION REPAIR AND YOU KNOW

THIS MUCH BETTER THAN I DO HAS

ANOTHER PROTEIN THAT IS THE

DAMAGE DNA RECOGNITION PROTEIN,

THE PRODUCT OF XPE THAT IS KNOWN

TO BIND TO THE APT DIMER AS WELL

AS -- DOES A BETTER JOB WITH --

THAN THE TT DIMER.

SO I GUESS THAT YET INDEED FOR

THE SAME REASONS THAT MER

DIRECTLY HAVE PROBLEMS WITH

LESIONS THAT DO NOT STABILIZE

DUPLEX DNA HAVE TRAVELED

RECOGNIZES THAT COULD BE THE

EXPLANATION OF TT DIMER.

AND SOMEHOW THE CELL TRIES TO

COMPENSATE FOR THAT BY BINDING

OF AN ADDITIONAL PROTEIN BUT

DEFINITELY INCREASED THE

INCISION OF THE SPECIFIC DIMER.

>> OKAY.

WELL THANK YOU.

LET'S GO TO THE UNIVERSITY OF

NORTH CAROLINA, CHAPEL HILL.

CAN YOU UNMUTE THERE?

OKAY.

ANYONE THERE?

YOU WERE THERE BEFORE.

HOW ABOUT UNIVERSITIES OF

KENTUCKY.

>> WE'RE HERE.

CAN YOU HEAR US?

>> YES, WE CAN.

>> THIS IS DAVE.

KIND OF A FOLLOW UP TO KEN'S

QUESTION, MAYBE, IS -- REALLY

WELL WITH THESE ADULTS THAT THEY

MAINLY DON'T PREFER THE

STRUCTURE MUCH IF AT ALL.

IF YOU LOOK AT LESIONS THAT ARE

MAYBE MINOR PERTURBING LESIONS,

IN YOUR RESEARCH OR SOME OTHER

PEOPLE'S RESEARCH PREDICT THAT

CERTAIN SEQUENCE CONTEXT IN

WHICH THOSE MIGHT FORM MIGHT BE

RESISTENT TO REPAIR.

FOR INSTANCE THEY FORM IN --

MAYBE THEY'RE MORE STABLE MAYBE

THEY'RE MORE RESISTENT TO

REPAIRS SPECIFICALLY IN THOSE

WITHIN THOSE SEQUENCE CONTEXT.

I THINK THAT MOST LIKELY HAS

BEEN THE GROUP -- DOING A LOT OF

MOLECULAR DYNAMICS SIMULATIONS

TO SEE THE CONFIRMATIONAL

FEATURES OF ADULTS THAT REALLY

ARE NOT QUITE RESISTENT AND THEY

CAN BE FORELATED.

BUT I'M NOT SO SURE VERY CLEAR

PICTURE HAVE EMERGED SO FAR FROM

THOSE INVESTIGATIONS.

MENTED JEUKSINVESTIGATIONS.

>> OKAY, THANK YOU.

>> THANK YOU.

PLEASE MUTE IN KENTUCKY THAT'S

GO TO NIHES RESEARCH TRIAL.

>> HI, KEN, IT'S MATT.

WE GOT TO WATCH YOU THE WHOLE

TIME.

IT WAS REALLY NICE.

>> SORRY ABOUT THAT.

>> I THANK YOU.

WE LIST UPPED.

WE OH WE LISTENED AND WE DON'T

HAVE ANY QUESTIONS BECAUSE WE

COULDN'T STOP THE VIDEO.

COULD YOU CALL THE BRIDGE AT

SOME POINT AND ASK THEM WHY THEY

WOULDN'T ANSWER THEIR PHONE AND

WE'RE EAGER TO DO THIS ON MAY

15TH.

>> YES.

OKAY.

FOR NEXT MONTH.

>> HOPEFULLY WE'LL POST THOSE

SLIDES.

PLEASE MUTE THOSE, MATT.

UNIVERSITY OF PITTSBURGH, ARE

YOU THERE.

>> CANNOT, WE'RE HERE.

THANKS.

WE ALSO ONLY SAW YOU ON THE MAIN

VIEWER BUT HOPEFULLY WE'LL GET

THAT FIXED.

IT WAS A VERY NICE PRESENTATION

BUT WE HAVE NO QUESTIONS AT THIS

TIME.

THANK YOU.

>> CHAPEL HILL, ARE YOU THERE?

OKAY.

THEY WERE THERE BEFORE.

>> YES, WE ARE HERE.

SORRY, WE ALSO HAVE THE SAME

PROBLEMS WATCHING THE

PRESENTATION IN A VERY VERY

SMALL SCREEN AND SEEING YOU ALL

THE TIME.

AND IT WAS A VERY VERY

INTERESTING PRESENTATION, I

APPRECIATE IT BUT I DON'T THINK

WE HAVE ANY QUESTIONS RIGHT NOW.

THANK YOU.

>> THANK YOU, PLEASE MUTE.

HOW ABOUT IN PORTLAND?

ARE YOU THERE IN PORTLAND?

HOW ABOUT IN BALTIMORE, ARE YOU

BACK?

>>ANYONE ELSE WANT TO

QUESTION?

>> I HAVE A QUESTION.

SO KEN, I HAVE A QUESTION FOR

CARLOS WHICH IS YOU SAY THAT

AAF -- FOR EXAMPLE PERSISTS IN

THE GENOME BUT THIS IS A BULK

ADD,.

ARE THEY REPAIRED IN ACTIVE

GENES PRESUMELY WHEN RNA

POLYMERASE -- REPAIR.

>> I ASSUME EXACTLY THE SAME.

I DON'T KNOW IF ANYBODY HAVE A

SPECIFICALLY LOOKED AT WHAT

HAPPENED WITH TRANSFUSION

REPAIR.

AND I GUESS THAT RAISES THE

QUESTION THAT PERHAPS ON THE

WORK WHERE THEY HAVE SEEN THE

PERSISTENCE OF THE ADULTS UP TO

SIX MONTHS IF YOU LOOK AT THOSE

GRAPH INITIALLY THERE IS A RAPID

DECAY OF THE LESIONS AND THEN

THEY REMAIN CONSTANT.

PERHAPS THOSE ADULTS ARE NOT IN

LESIONS THAT ARE TRANSCRIBED AND

THAT'S WHY THEY ESCAPE TCR AND

AT THE SAME TIME THEY CANNOT BE

PROCESSED BY GLOBAL GENOMIC

REPAIR AND WHILE YOU HAVE IT

THERE AFTER TEN MONTHS.

BUT I DON'T THINK ANYBODY HAVE

DONE THE EXPERIMENT.

>> OKAY.

ARE THERE ANY MORE QUESTIONS?

IF NOT, THANK YOU VERY MUCH.