Ourania Chatzidoukaki The functional link between the DNA damage and innate immune responses in macrophages Summer school-Chromatin3D Heraklion, 1st October2016 In our lab, we focus our studies on Nucleotide Excision Repair, a highly conserved pathway, that removes DNA-helix distorting lesions caused by UV light. Ourania Chatzidoukaki Garinis Lab

DNA: the unit that carries the genetic information and transmits it into the progeny. DNA is an iinformation storage macromolecule that contains whatever is necessary for the growth, maintainanice and function of a living organism. And what is really important is that this kind of information should tranferred intact to the progeny.

The DNA damage signaling DNA damage agents Cellular metabolism UV light Ionizing radiation Chemicals Replication errors The DNA damage signaling can lead to chronic inflammation However there are a couple of factors that can destroy its structure. More specifically these dna damage agents can be uv ight, ionized radiation, chemicals, replication errors and so on. Recently it has been shown in my lab that dna damage can induce inflammation. This happens because dna damage agent can induce or interact with proinflammatory genes.

Chronic inflammation Cardiovascular diseases Neurological disorders Metabolic disorder complications Cancer Diabetic complications Bone, skeletal, muscular diseases A couple of years ago inflammation has started to gain popularity. In fact a times cover point out the crosstalk between inflammation and various disorders. In fact inflammation is a protective response involving immune cells, blood vessels, and molecular mediators. The function of inflammation is to eliminate the initial cause of cell injury, clear out necrotic cells and tissues damaged from the original insult and the inflammatory process, and to initiate tissue repair. Indeed chronic inflammation can lead to neurological disorders….

Should we care about the mechanism of DNA damage induced inflammation?

Aicardi-Goutières syndrome Trichothiodystrophy Cockayne syndrome similar Neuropathology and type I IFN immune responses The significance lies in the similarity of patients symptoms Thrichothiodystrophy:is an autosomal recessive inherited disorder characterised by brittle hair and intellectual impairment.  Cockayne syndrome:  also called Neill-Dingwall syndrome, is a rare fatal autosomal recessive neurodegenerative disorder characterized by growth failure, impaired development of the nervous system, abnormal sensitivity to sunlight (photosensitivity), eye disorders and premature aging Aicardi-Goutieres syndrome:hich is completely distinct from the similarly named Aicardi syndrome, is a rare, usually early onset childhood, inflammatory disorder most typically affecting the brain and the skin (neurodeve

Ercc1 -/- express pro- inflammatory genes Garinis et al., Nat Cell Biol 2008

Innate immune response Aim Metabolism Innate immune response and inflammation DDR Disorders DNA damage Ageing How ? Cancer

How are we going to tackle this problem?

Bone marrow differentiation with GM-CSF System Bone Marrow derived Macrophages isolation Day 1 Day 1-7 Bone marrow differentiation with GM-CSF Bone Marrow BMDMs Mouse models Ercc1-/- Xpa-/- Xpc-/- Csbm/m C57BL/6 Treatments Mitomycin C (10 μg/μl) ATRi (10 μM) ATMi (10 μM) H2O2 UV (20kJ)

Techniques Cell cultures Imaging Proteomics

Result 1. Knowledge 2. Application Inhibitor

Live Longer, Live Healthier I believe that the take home message is that we should manage to live to live healthier and long and this would be achieved only investing in science Thank you very much