Maria Moriel-Carretero (CRBM) - General Principles of DNA damage sensing by (lipid) membranes Centre de recherche en biologie cellulaire de Montpellier
Donnerstag 15 Januar, 11:00 Passed
The DNA Damage Response (DDR) is a complex signaling cascade elicited in the cell by damaged DNA, orchestrated by apical protein kinases, assisted by sensors and effectors. The two master kinases upstream of the DDR, ATR and ATM, are thought to mainly respond to single-stranded DNA and double strand breaks, respectively. However, “non-canonical” types of DDR have been reported (compact chromatin, mechanical or oxidative stress, among others), meaning that there exist stimuli equally capable of launching the DDR, yet in the absence of actual DNA damage. Overall, it remains poorly understood which is the actual signal, or signals, engaging these kinases. Building on the knowledge that ATM and ATR belong to the phosphatidyl-inositol-3-phosphate (PI3P)-kinase-related kinase family, we interrogated in the past if ATM and / or ATR can bind to, or be influenced by, phosphoinositides or other types of lipids. Of note, ATR has been found, in at least four previous studies, to sense the physico-chemical properties of phospholipids. We have discovered that ATM binds phosphatidyl-inositol-4-phosphate (PI4P) at the Trans Golgi, which allows it to remain anchored in an inactive (and non-phosphorylated) status. Activated ATM working in the nucleus can be titrated by the Golgi if PI4P levels at this location increase. Reciprocally, if PI4P levels decrease at the Golgi, ATM becomes more available to readily respond to DNA lesions inside the nucleus. Concerning ATR, we found that ATR combines its ability to sense DNA damage and phospholipid profiles to finetune the response to DNA lesions in a manner dependent on metabolic cues. We are confronting at present an even more surprising (yet simple) rule: DNA damage can be “felt” by membranes without the intermediate action of a DDR protein cascade. Inspired by compelling examples occurring in the mitochondria during the quality control of mitochondrial DNA, we are defining now general principles of this DNA-membrane signaling axis in the nucleus. Overall, I will discuss how the lipid profile of the nuclear envelope and other cellular membranes, which evolve in time and space, exerts a control over the response to DNA damage.
