Welcome to the NH DNA repair interest group, monthly
video conferences. Today we are very happy to have
a doctor, Nelson Gkara.
To be the guest. Before we proceed into the introduction,
I only like to, encourage everybody to join our young
investigator talk next month in November, the 12.th
Wait, when we, we will have a 2, distinguished award
winning young scientists to share their story.
For today's talk and Dr. Nelson Gera is a distinguished
scientist whose research focus on understanding the
regulation of innate immune responses and DNA repair
Currently, Dr. Idihara held the position of food professor
of microbiology and molecular infection immunology at the
Medical Center University or for Frankenberg.
In Germany. Since, 2,022. Dr. Dakara also serve as
an associated professor at the Winner Green
Institute at the Stockholm University since 2 2 2,019.
Dr. Khakara's academic journey begins with bachelorship in
biochemistry from Jomo Kenyatta University of Agriculture
and Talking Technology.
And after that, he has been, research research shows in
Kenya, Switzerland and Germany.
So he's, So his expertise in infection immunology and
molecular mechanism of horse defense has made him a leader
in the molecular mechanism of horse defense has made him
So before we start, I would like to ask. The audience
to please, in put your questions if you have any in
the chat box and we will go.
Through them after the talk. Dr. Kakara.
So, thank you very much. For the invitation to this. This
delete cloud from I because this is a group on DNA they have to
I have a confession to make.
I actually don't consider myself an expert. And that is
probably the 1st invitation to to. To a seminar series in So
my actually interest in January.
The stems from an interest in understanding. Post
-defense system. And if. Let me talk about,
We can all agree that the net immune system and the
DNA repair system. The primary defense against.
It's external and internal stress. So they needed
new system. No, man, we organize infection, about
what we call the pattern cooperation receptors and
We then mediates pathways and clearance. As well
as the entertainment. Us plus t-shirt in there.
For example, the injuries 2 module infections too mark the
net system also. With us and activations and that pathways.
So as 30 min, as there are said, we are be affected.
And as you all know, the DNA system on the other hand is
a set of signalling pathways.
We're out to get in response to DNA damage. I their
function is of course to the Yeah, but we solving
the integrity of the cell.
And of course the
So there's a lot which is be known about the netting
system on the DNA system. And much of our understanding
of the net immune system but the United system.
Stems from decades or research. Looking at these
systems. Separately. But it's becoming clear from a
can say The last few years that they need new system.
And the DNA system. Highly interdependent. And that
defects in the innate immune system, or DNA systems.
Actually underline many of the health afflictions for
example, infection or immunity, cancer, new regeneration.
And many of the aged, disorders.
And as I said, it's becoming clear that the innate immune
system or the enterprise system are highly independent.
And this will be becoming clear that, regulation of the innate
immune system at the United system involved a developing
set of signaling molecules.
And in this talk, I will be highlighting some of
the key molecules that we've been focusing on.
And these these molecules. Really sit at the intersection
between the net immune system. And the DNA repair system.
And these molecules are what we call the intracellular
DNS sensors. That is C and M link resetters.
And, so that's what I'll be forecasting. So 1st
of all, what I think is Fossil at DNS sends us.
As I says, there are 2 well characters, family members of
the intracellular DNA sensors.
The 1st one is C, which is start a cyclic m. And the other
one is a family of receptors known as, So see GAS is
actually a DNA bonding enzyme.
We are all binding DNL. Catalyzes the secularization
of ATP and GTP into CCOM.
And this sec is a very important activator of the
new system. It triggers downstream events by binding
to an attack on us being and that results in the in the in
The aim like this up is a large family of unique
planning proteins. In human we have 4 members.
In mice we have 13. And the best character as
of this is a DNA banning protocol is known as M 2.
And its function is once its bands with It activates a
complex numbers in Flam. And this influence is important for.
Mediating cell death programs. As well as processing.
Protolithic processing or interlinking one,
farming side of clients.
So now I say my interest in dinner repair really stems
from. A desire to understand.
And when I talk about post -defense, I often start
by these very old time testing military maximum.
But he's to be prepared for work is perhaps the most effective
means of preserving peace.
And that's happened to be true for the new system.
You see the new system. Is constantly wrapped up.
As you all know, you know the new system does not
like I've been waiting to be attacked before it responds.
At any particular time in our bodies. I was, as constantly
produced, even in the absence of infection or engineering.
And this constitute or this background production
of inflammatory cycles or interference. Is very important
for priming the immune system.
Keeping it in a wrap-up mode. So that will be an accountant
section or we're engine and the immune system is able to
react in a very fast moment.
And these, consider production side to clients. It's
very important for the new system because even subtle
changes the production of the cytokines can have a
In response. And that means that if for example If you've
been have a slight decrease. In this base of production of
side What will happen is that your new system will be a big
And you're likely to be grown to be more
acceptable to infections.
But on the flip side, if you have enhanced production,
consider production of cyclone interference. What happens
is your immune system It gets into an older drive.
So which means that if you are infected, your encounter
injury. What happens is you hide, but yeah.
And this can be pathological.
As though one of the fundamental questions that actually when
I started my room meeting as bad is to understand what are
the mechanisms that underline that regulate the expression
And when you talk about what really primes immune system,
I think it's sometimes good to take a step back.
And even us what is the new system?
You know, the leopard definition, the near system
we can say is the ability. To respond to stress.
And what is stress. I mean, stressed many, many things.
I mean, Let's just be micro -gadi rooms as you all know.
Stress could be mechanical stress, you engine your
knee, you have a swelling. And that is inflammation,
that activation system.
Stress could be extreme temperatures. To be
a technical portion.
But for for many years, when people have been looking at
the new system, people have always been focusing on my call.
But if you take a moment and think, my probe
invasion is probably the most reason stressed in
the evolutionary clock.
So that you, but then you can also start it. What is probably
the most preliminary module, the most constant stress.
But our ancestor has to deal with since the beginning
of time. The most concept stress. That, probably has
contributed to shaping.
Our new system to what it is today. And
that brings me to DNN.
So DNA damage as you'll know is probably the most cost of
stress in all live forms. It c
ould be from similar metabolism.
We eat or we generally have to option spaces. We
can cause DNA damage. You could be from UV Live.
Will be ionizing radiation would be environmental chemicals.
You could also be for example because of replication errors.
It could also be my pro -canism. Macro organisms are
not produce. Products that can actually cause DNA damage.
Awesome, for, for example, wires, can also damage the end
by intercolating to the end.
And now, for example, now that our genome has been
sequenced, very clear that our DNS replate filter elements.
W e just really a clear signature.
You know, on Cisco Bust. So based on this reasoning
based on this backstop And then I was asking what the
See that really constantly keeps the immune system. In the
rep. So in in high organism, one of the key companies
would be enterprise system.
Is a kindness known as ATM. A lot of function in ATM
results in a very complex disease known as attacks at
a language does in over 80.
And at that time, more than 14 years ago, I thought maybe
This disease could be modeled. This disease could be a
very good model for starting the impact of DNA repair.
And the immune system. So, 80 attacks it, a, is a,
is a man system disease.
Correct as a bad one has to console. Neural
generation accelerated aging growth retardation.
And at that time, I was it was very curious because when we
have to breathe through the in between the lead feature.
There are reports that this antipation also displayed
a variety of auto neon inflammable diseases.
Or female types whose etiology was unknown. So then
the question is why should defect generate the results
in spontaneous information?
So some of the early experiments that we did was to look at
patients. Take the serial from patients, attack the patients.
I'm looking to see them. And one of the things that we found He's
that in this in this theorem they have very high interferon
and also we've been we take the self in this patient and
And nothing inflammatory cycle points. And when we infect
itself from these patients with virus like bicycular
stomach that is virus.
Then they sales from the stations. What a
system to infection.
And 80 patients are very few. So what we decide to
do to really do make aistic studies. We resorted to,
to my, knock out mice.
And what we also found that if you have sales which lab have
elevated production. Okay.
And that if you change this mice with a and this master
assistant. We is nice, right? But on the other side, if, for
example, also challenge these animals or cell phone this, 80,
What you see you have amplified production of interference
other side accounts and the flip side or the downside of
this is that this animals are highly sensitive to services.
So they tend to die faster. So then we could summarize that.
It appears that defects in DNRIT that are accurate results in
I have a active immune system.
That is protective against viruses. But this technological,
which means that if you have defects in DNA repair.
These days of production of cytokines, which is important
for having up the immune system. All of us suddenly
have, you know, it really, you have elevated, you have the
It really goes out. And then the question was
What causes the spontaneous, innating and triggering
in the absence of
The simple hypothesis then we heard is that This convenience
inflammation we have for example in 80 patients.
Is because of accumulation of DMM in the absence of
the DNA. And this DNA can somehow be recognized
the new system as stress.
Of that country of inflammation. So moving beyond the education
or ATM. Another way of testing this hypothesis is even the
Watt app situation if we use DNA damaging agents we
And indeed what we see if you expose sales to radiation,
you induce interference. We also expose a sales to a Tocco
side, a chemotherapy agents, and which causes DNA damage.
You see you also use But also provide me the Interferon system
when you let them cheleny sales.
With viruses you have an and the consequence of that is
cells which have been exposed in in the dynamic agents
are highly resistant viral infection, which is rather
In sales that are the
So based on this, it's clear that DNA does
problem with the new system to enhance and divide.
Then the mechanisms. So how does Genta make this us in
activation of the new system?
And which innate new pathways are and So, so innately
inactivation. Or at least activation of the Remind me
of cars about 3 families.
Oh, we need to meet receptors that are on the surface. Of
the set. And also intracellular receptors like Variga,
which senses are, are in it.
Or the C gas which I I talked about early. And so what we
did, we screen mice which are defective in these pathways.
And what we found that Mars which are defective in this
adapter for this thing. Who are unresponsive, could
not produce interferon in response to radiation.
Meaning the DNA damage. Up against the new system about
interest in the Sensor.
So, DNED, I might go casting the new that time it was thought
that this intracellular DNS sensors are in the cytosol.
So how does then the stress inside the nucleus results
in a duration of these receptors in to cut the story.
Short, what we found that when you have DNA damage. What do you
have difference in DNA repair?
What happens is that DNA is getting into the cytosol
from the nucleus as we can see for example in
cell phone 80 patients.
And then this DNA is sort of, you know, recognized like a
cell which has been infected by a virus as a bacteria.
And this is what this is what then at least the activation
o f the CEOs. And in collaboration
with the emerald separate if he's 16 and this then
And so this is the model that we propose. to explain how the
inademic and the immune system.
We propose that at any particular time Of course,
ourselves exposed to DNA damaging. It could
be replication stress.
And because of that, we constantly have No, DNS. For
the nuclear to the cytosol and this is essential for
priming the new system.
And that if you have OB exposed to DNA damaging ages like
radiation or chemotherapies. What up as we have an asked
accumulation of being a damage.
And in has release of beginning to the site or so. I then
has activation of the Sega Sting and the AMlet receptors.
And this results in really driving up the new system. I
make us making us hyperactive. To, both, external as well
as internal stresses.
So this this this work is already published in years back
now. And, you know, so since this work has been published,
I think it's, now clear that,
It's accepted that this is probably the principal
mechanism behind the DNA image induced immune activation.
And this is significant because The idea that DNA damage trigos
inflammation is actually not new. probably, you know, when,
radio up to the substance of what is covered, way back more
One of the of the feature which was recognized is
that we put radium on the pocket. You had inflammation.
So inflammation is a whole map of DNA damage. But the mechanism
for how I'm doing it in use inflammation was not clear.
And it is becoming clear that the activation of this
intracillity in a census is the principal mechanism behind this.
And, and so, and so DNA that I'm making this inflammation
is both good and bad.
It has benefit imposed. As I've explained, D and I'm
making this inflammation can boost antimacrob.
And it's also clear that DNA damage use inflammation about
the intracellular DNA sensors.
Underlies the therapeutic efficacy or many of
the anti-Kenser agents.
For example, radiation came up to happen.
And of course, DNA emerging agents, DNA damaging
and use inflammation is also pathological.
Was it drives many of the pathology following accessible
radiation. A key transition syndrome for example.
Oh, also drives many of the pathologies that are
normally found in patients. That love the United there.
I need It's also clear that as we age we lose our we need
to repair the DNA breaks.
And this, accumulation of DNA, damage and activation or C
is what actually contributes to the aging process.
And so, whereas the any damage induced inflammation,
but the CIA scene can also promote anti-tuma immunity.
In other instance, it also been shown. To promote
metaphysics. They can promote, a team of progression.
And it's at the moment it's not really, clear. I did then.
They the conditions, under which CIG has the most
entertainment unity and timber progress is not very clear.
And these are not that many labs are interested in. But
moving forward, the point here, and I wanted to be one of the
techho message is that DNA is a case or intrinsic stress.
We need a new driving. And this priming involve
optimization or int but the DNA that is came from the
nucleus in this side as well.
So when we talk about, you know, so I've been talking about
this intracellity in a census.
Now I'll and they are all in netting in activation. But
now I'll receive the gear and talk about the role of this
introscelled in a sensors.
In that. But before I get into that, I will charge
all a very important aspect of the immune system.
And that is self non self discrimination, the immune
system. How does the new system discriminate itself from self?
So 1st of all, as I've explained, be very clear
from from from the previous slides. The DNN is a very
important you'll use them.
And that. DNA also happened to be the most abundant
macro molecule in the cell. One can say so.
And perhaps one of the things that I did mention this
introcellular DNS sensors CIGS and M blood receptors.
Ultra, it's coagma has DNA, irrespective of the sequence,
which means they can recognize both microbial DNA as well as
No, Oh, DMA is a very important activated on the admin system.
It's very abundant in the cell. I see that's connected.
But under healthy conditions.
The sales does not go up in flame. So then how
how does the new system really discriminate itself?
Another 17. I'm for many years until very recently
actually. One of the key principle of certain and self
-discrimination with the system was based on the assumption.
Does this DNS sense or see here's an emitted
receptors? I exclusively localized inside the zone.
Away from the TN in the nucleus. And that these receptors only
get that theed, following infection with microbes.
Or when we have DNA and the DNE leaks out into the site
and then these receptors are
Another way a very of a simplified way of looking
at this is to imagine that that these receptors which
bind DNE are like us or and the DNA is like explosive.
And the only reason why the sales and is not going
up in Flem is because the gasoline and explosives are
in separate compartments.
At least it was not like that.
But when we started looking very carefully. What we found
is that this intracellular DMS receptors that bind DNA and
we seek us here for example.
This and all the end like receptors. All of them
were actually in the new. For example, see Gauss
was mainly the nucleus.
EFIX teams making the nucleus. The only one which
was in the nucleus and is M 2, 2, so in the nucleus.
So all these receptors Which buying DMA are actually in
the nucleus? So then the question is what really
prevents this new PR, from reacting to economic DNA?
That's 1. The other what is the function of this DNS
sensors in the So this question about the past question, what
prevents nuclear DNA sensor from reacting to genomic DNM?
This has been addressed by recent studies and I'm not
gonna summarize this. So following our demonstration,
the DNS C gas is nucleus.
There are so many papers that came up, for example,
you know, 3 of them in nature that can within one
month of them in science.
But just to summarize, what we found out is that SIGAs
in the nucleus combined with the pro and by binding that
into the chromatin, it's out of trapped in an inactive
And that's why that's not figure information. And that's
all I'm gonna say about this.
No, I'm gonna focus on what is the function.
Oh, this DNS sensors.
In the nucleus. So when we identified that these
receptors are in the nucleus. Our interest at that time.
Was the impact of this receptors. In host response
to Gino's toxic stress. And if we, for example, we analyzed
sales, we will have seek us.
So, What and we look for sell that. What we found that
says that and seek us or aim let receptors What a system.
In other words, that SIGNs and emland receptors are
actually potentiates.
DNA that we do sell it.
And this the prompt had to really look what about
what is the impact of this receptors Indian everywhere.
And then we decide to use a commit and when we compare the
repair of DNA breaks What? I see Ga, we could see that the
S ika's knockout sales peric and a
As I said, SIGNS is an enzyme which symbols a secum and
Cgum 10 signal by the sting partners to reduce inflammation.
And the question was So this results essentially means that C
does. Is an inhibitor of B. But if you don't have it, you have
enhance without your networks.
So therefore we're interested where the seekers in hit the
DNA repair about this thing But when we look at repair of
the DNA breaks, we compare, we found that sting knockout cells.
Can't If he shouldn't like the Walt up sales. Which means this
new function. Oh, SIGNS NGOs in DNA repair was independent.
Of the of the canonical function of the CIA in that immunity.
And now we also look at the aim like receptors. You know,
emland disceptors actually classes in one lockers.
In the human and in mice and they are mice which allow
all the envelope centers. So when we look at the ability
of cell phone, in black, what we see, and this is a
You can see that says that like the am receptors. Could
resolve the DNA breaks fast.
And then you wanted to know to able at receptors
also in P genome repair. Via a bit downstream.
Adopt and only compare the repair from A/C, they prepare
the DNA breaks much like the wild time, which means
again the ample receptors.
Can in pair the Gitome repair independent or the
function of these receptors in the meeting system.
I we went in people. As you're probably born marrow
suppression is is is a major cause of mortality.
For example, following radiation. And so to
really show or determine whether these, Inhibition
of DNA by these receptors.
See, us and, and name like you set us. So it's got
other ones in the people.
We exposed mice to radiation. The Cgas knock out and em blood
the septuna through radiation.
I look for bone marrow and if I see you have one
more operation. 50% within 12 h as you can see here.
But when we carefully type traded, we found that my,
with emerald sectors was significantly the system.
To radiation induced Bonima.
Okay, so from this we could complete that actually
see us and MLAD receptors are negative regulators.
And has accelerated DNA damaging inside.
And then of course then we this also triggers to really
ask what is then is the impact of this DNA sensors.
Oh, the sensitivity of GANSSA. Sales to DNA damaging
agents. And here I show you, for example, and I didn't
show you for the data for the name like Reset Trust.
What we found is that Kancer cells which large the SIGRas
were actually highly assisted.
To a doctor. And here I have to mention that many of the
council says a half down regulation in the expression
of So I'm suggesting that probably lots of SIGNs could
Based on this and we decide to look for example
in publicly available data, data for patients.
Following radiation of chemotherapy. And one of
the things that we found persistently is that, patients
t hat really show lower expression
So they have no explanation of or the M 2 and they
have prognosis. And this I guess that the DNS has a C
does it in black receptors.
Do portation, the the tumour, effects or DNA,
So mechanistically, how do this seek as an emblac?
Is that that in PG G.
Here I will not go into details. I will only
summarize here. As you'll probably know better than me.
One of it, you know. Chromeat instruction is very important
for the timing, you know, the outcome of being and
and one of the early events following the endemic is the
To allow for generic factors to be reproved.
So in somebody what we found is that the end black
receptors and see us by binding directly to the chromatin.
And then that wasn't self-. What these receptors
do is they impede this chromatin relaxation.
Which is important for the regroupment or DNA
factors. And by so doing and by inhibiting DNA.
These receptors. Absolutely.
You know, that was one could also speculate that problem,
this DNA sensors. Could be potential determinants.
Of our marker for predicting the radio sensitivity. Oh,
And as I mentioned before Many of the classes actually have
down regulation in expression of PTDNS, DNS sensors.
And that would be one of the mechanisms of which.
Because I says computer system too. To So in summary.
The message that I wanted to hear is, of message
number 2 is the DNS and SSC does an emblad set.
Have these things subsilla function? In the site also,
the important coordinating in activation in the in the
nucleus, the regulators of chromat instruction repair.
And he's 3 other from many many studies that this you
know defects in this DNA receptors have implication
in many disease in many diseases, including infection.
Vote inflammation class and new regeneration sentences
DTC. And we think that this distinct function In this cycle,
in magnetic in activation.
And in normally there would underline. The
multiple, effect on health.
And so based on this, and again, I want to like the way
I started, I started by, you know, real stating that is
clear that the new system.
The DNA repair system, highly, there's a lot of prostock.
And there are many molecules at the intersection of this.
Some of them we publish on business one ATM one. And
now I've been focusing on the SIGNS and the MLAD receptors.
Yeah, but. These receptors are not only, 1st of all,
they're important for driving DNA damage genes inflammation.
No, I've also shown that these receptors are also
important. Manipulating the repair of the EMM breaks.
And then. The company issue is, you know, to be able,
as I said in the beginning, that the new system and
the dinner repair system or details in this system.
Underline many of the health conditions. And can we find
a way of modulating the new system and being an array
system simultaneously?
And one way would be if we can target some of
the monarchies and the intersection of these fields.
Then the question is because he does and him like receptors
seem to be involved in the regulation of both systems.
What if we can find inhibitors of these figures? And
internet receptors. Can we dump an inflammation?
And, but can we? So following this, line of thought, we
decided to read the screen.
For potential inhibitors of this. And what we did and we
focus on seekers, you know, the inhibitor of the seekers.
And then we found a compound. That when we incubate
themselves, it could in heated induction interferons.
Following activation of CEOs. And that is the structure of
this compound. And for the chemists of you in the audience.
Probably you know what this compound is. But
I'll, I will of course, you know, tell you later.
And so this compound, when we give this we
This is, SAYS with this compound. What we could see
if of course we could reduce the internal induction all
the way in the transaction.
And when we also incubate ourselves with this compound
and do a comment assets, we can see we have Okay.
Which is very nice and this very consistent with what we see when
we don't have CIGS in the cells.
And this is when we go into people and we get this company,
and look for inflammation following radiation, you
could see that drug X would of course reduce interfererow
And with the count the it could actually partially protect
against irrigation. And look at survival, the drug X could
actually extend survival.
So which means that drug apps by a an impeding inflammation,
it can actually promote the survival of animals.
So who are excited? But then we try to do additional experiment
and this was a disappointment because We decide to see
whether is it really specific.
And we found that, when we integrated sales with draft
X, and stimulate the sales at the other is like taller
accepted 2 All except at 3.
Drop X could still in heap it. Activation of
the new system which means This is drug was actually
not really specific for.
We'll see where it is important. And then we also ask what about
repair? People also, just as this had to had 2 9 3D sales.
Don't have seen us and we check what are you know
this is draft can promote the non-repair and visas.
Using this reporter line. And you can see these drug
ads could actually potential genome right there. In this
So it was not specific.
But the most important thing is It's somehow in his inflammation
and it and was about X.
It's asking. The ask me, as you all know, is probably
all the drugs in the history of human medicine.
It's. Is perhaps the most widely used travel inside
Viagra. And is commonly used for the treatment of
pain, inflammation fever.
And cardiovascular diseases. It has also been linked
to. Cancer prevention.
Unless you all know the best mechanism of our
screen. He's inhibition prosta granting production.
Bye blocking the cycloxiness enzymes, box one and box 2.
And this is what was known.
And as I said, it's clear that Aspen, promotes the normal care
and protects against radiation.
And is what I just showed. Now the question is what
are the mechanism? How does asking acceleration?
So, and they can summarize because I don't want to be in
the interest of time. What we found anyway is that One of the
key target of us is the HISTONS.
But us will actually acidulate Eastern. Actually even more
specifically the Houston h 4 k 16. Basicatelating EASTON'S,
what happens is actually promote this competent relaxation, which
Vixam Bracca one. And that's why when we are exposed
to asking. And we eat.
Aspen and you see this in evil as well in vitro. Is
that by-satulating the system?
Askpen really uses the chromatin relaxation.
Promoting improvement in what underlies the protective,
effect of our screen.
And at this and we think that this the ability
to accelerate you number and damp inflammation.
Is a possible explanation for the concept within the Maybe
this is an exaggeration, but at least that's what we are going.
With.
So anyway, in conclusion, as I said, is the new system
and linear repair system are interconnected and
that may be concentrated on on this DNA sensor.
See as an emperor. I'm sure that this malloc is really
sit at the intersection.
Of these defense systems. And many other molecules also are
in the tensor intersection here of course is not only
C and M black receptors.
And we are still persuaded that. That actually targeting
some of the molecules at the intersection of the
mu and DNA repair system.
My providing might provide a means of manipulating
both the new and DNA repair system. In the management
of very complex, diseases.
Our request to find specific inhibitors or C does an em like
receptors. Been turned out.
But, but at least it enable us to find a new mechanism of our
screen. That, and ensure that aspirin actually can modulate,
condemn the inflammation.
And promote and that usspring would be one of
the drugs that could be used. In manipulating this.
To the phone system, to improve that.
And with that, I mean, that's all I had for
you. And, oh, hey, sorry.
I think the last slide for that more argument
I must have deleted by absent. I'm very sorry.
And that's just about it.
I you still there?
Yes.
We are still there. Sorry. Okay, we have questions in
the chat. So I encourage the rest of the audience
to put their questions in.
Okay.
There are 3 questions there, vibrant ski, that I'll just
read the 1st one. And it's from the 1st part of your talk,
which is our DNA damage induced doubts, a DS Dubstone DS DNA
Can you say it again, please?
Yeah.
And I think it's our DNA damage induced. DSDN, I don't
know whether it means double strand breaks in DNA enriched
for retro-transcribe DNA from competitive elements.
No, no, I think.
And it means that. Maybe Whitsky, could you, Banel
could do Lip Ripsky?
So good.
I probably understand. Hey, let me repeat the way I understand
it. The question is what.
The DNA that we find with the cytosol following
DNA damage. From
Yes. Yes.
It's, you know, because we try to analyze this and it's,
it's, completely unspecific.
It's from all over. Because the elements are highly
represented in our genome, we also find them there.
But the other thing I mean this one of the questions
that we asked before He's that when you have inflammation.
And you do have inflammation for One of the things that I have to
be activated is a retro element.
So red elements, if I if you put sales with, for
example, bacteria or LPS.
You see a So you do see an increase expression rate or
elements. But we think that the retro element is a consequence.
Oh, in your I'm not, of us. Of course it contributes
to amplify. But at least we have a issue on that.
Element expression is a consequence of union activation.
And I don't know what I'm answering the question.
Okay, I'll go with the second question from Risky.
Does a C gas binds to a nuclear question from Risky.
Does a C gas binds to a nuclear lamb inbound DNA
and that keep them inactive?
The C does bind to nuclear.
Lamb inbound DNA.
I don't know.
I don't. Because the thing is, What happened is that
in the chromatin, see goes.
Actually, not only binds DNA, but it binds the And that's why
it's inactive in the nucleus.
So if you have promote in SDN name, see guys will
ban it and it even bars with strong alphabetity.
And that's what really drops the CEOs in an inactive, a
confirmation in the nucleus.
So with L, yeah, that's all I can say about this.
Okay, in the interest of letting other people have a. Chance
to answer a question. Because Ritzki has another question.
Yup.
We'll get back to him later. Somebody, I phone 1 9 says
fantastic talk. Do you already have evidence for the
aspirin effect on chromatin?
I think you went through that very quickly. Maybe you
could give a few details.
Do we have heavy deaths? Yes, we have evidence. We had
reporters. Why we could actually when we we were expressing
us and we could we could see that it really impedes for
And will be knock out. See that then you have
more, you know, chromatin.
Oh yeah, so we have everything for this.
And that's in your 2023 paper that you cited.
Yes.
Okay, okay, great. We have a next question from, Suha,
Shaman, does, DNA damage or genotoxin treatment
alter C gas expression in normal and cancer cells.
You know, I think probably good because 1st of all, as I said,
many of the councils, you know, you have, suppression of Ciga's
expression, that's 1 thing.
And also see gas was initially identified as
one of Inferron needs genes which are normally expressed
following immune activation.
So again, because in your activation. Oh, DNA damage
country called near the immune system. And I think the new
immune figure in put in don't figure the expression of So it's
But in many of the cells, you do still have basal
expression of the seagulls, but it could be the expression
could be increased during inflammatory conditions.
Okay, there's a question from Daria Bogdanova. Sorry
about the pronunciation.
Would you please repeat your hypothesis about
how sea gas discriminates self and non self and DNA.
So what happens is that C gas normally is
activated to produce. No, it plans to make a DN.
Then it, But when it advanced to DNN, which is, but you
have systems. What happens is actually there's not bound
to the DNA but it runs very strongly into the histogs.
With a very high. And then by adding to the distance,
it sort of dropped in an inactive confirmation.
So essentially, Sort of, Scarbank is the Cgas in the
nucleus and really drops it.
At least that's 1 of the hypotheses out there. We
do have and this not the only mechanism, at least
that's 1 of the mechanism which has been reported.
That it's because of the competition with the
Great, I think, there is, there are a couple of questions
from the panelists. I see you can raise the hand first.st
Ken, do you want to? Ask a question correctly.
Yes, I'm, I'm, my video is blacked out, but I will talk.
In the mystery. The, this is a wonderful talk. Start my video.
Here we go. Heara, yeah. It's a wonderful talk. You've studied
particularly a taxi at which is a DNA repair deficient disease.
We study a couple of others that where we've been
puzzled for many years how they get inflammatory
and immune reactions.
One is zeroderma pigmentosum. And depending on which
mutation they have. If they have mutations in the XPC
gene that's involved with the global genome repair.
They have normal sun sensitivity. Where is if
they have mutations and other repaired genes like XPA or
XPD that are involved in transcription coupled repair.
They're exquisitely sensitive to the sunlight. And so clearly
there's some role between these particular mutations and the
inflammatory reaction to sun.
And the second disease we study is trico of the xeroderma
patients have a 10,000 fold increase in skin cancer.
All of them do. So that's 1. The other one we look
at is, tricophiodistrophy.
That has a different mutations in the XPD gene.
And then the XP patients do.
But they have a multiple infections. Are they often
die of infection? They have, we publish papers on immune.
The fact that they have immune problems. But we've been
working with them. We try to get the immunologists here
interested in finding the exact.
Issues there and they haven't found it yet. So that's another
area that's Another fertile area for, studies like these.
And I'm really impressed with your study here. Thank you.
Yeah, I guess one, that's thank you very much. I just want to
point out it gets very complex.
When we look at the defects in DNA and the immune system.
Because, we also have to remember the DNA repair
is also very important for the development of the
And so you could also have immune deficiencies because
of the in some of the DNA and it gets very, very complex.
And, yeah.
Okay, we also have a question from Vilbore. Oh?
Yeah, thank you. I also really enjoyed the talk. I
really nice. Overview of this interaction between the
immune system and DNA repair.
I have specific question. Interestingly, these 80
patients very often die from lung disease. Is there
something is a special something special about the long?
And this innate immune system pathway or something.
That explains this.
Yes, so we we did publish a pipeline immunity in 2016 on
this. And one of the things that we found in addition
to defects in DNA there ATM is very important for
And what we found that if you have a lot of oxidative
stress. It oxidizes. Some of these inflammation components
which are also very important for antibacterial immunity.
And this one of them and then this we really did a very I
think we did a very good work we control these I think
that's 1 of the mechanism because of oxidative stress.
Do that is the long.
Because of the alarm. But also I think it gets very complicated
also and I think also what happens because these normals
the poker's new morning is back.
Infection, right? What I think and this is so what
happens when we get old when you go to intensive care unit
What ever even as you have you're more likely to die
of lung but due infection. And this is because of, I
think, neurodegeneration.
Because if you look your plug function that you can
breathe cough and all that you know and you're not able
to constantly expel, for example, the new CAS and all
Over time, you develop this buy of.
And this biofilm, of bacteria, it can hand up
killing. So from, so that's 1 of the aspect I think.
Yeah, very, nice idea. Yeah, thank you. Enjoyed
it. Thank you very much.
All right, so with, with the time restrain, we probably
have to stop here and, for the unanswered questions,
we will reach out to Dr.
Keykara through email and, the, and the later. Again,
please join me to thank, Dr.
Geekara for his wonderful talk. And we're looking
forward for more of your wonderful investigation
and more interactions.
Thank you.
Alright, take care.
Thank you, Thank you. So.
Bye