Sensing and repair of DNA interstrands cross-links

Ziel

To give further insights in the knowledge of the process of genomic stability maintenance, we will focus our proposal on the understanding of the early events involved in ATR and Fanconi anemia (FANC) pathway activation after DNA interstrands cross-links (IC Ls). We have established that ICLs activate independently ATR protein kinase and FANC corecomplex. Both participate, to the activation of FANCD2 that allow full S-phase checkpoint and DNA repair cohordinating homologous recombination events.

We want to determine the precocious events leading to ATR and FANC core complex activation after ICLS. The RAD9, HUS1, RAD1 and RAD17 proteins are key elements of the DNA DAMAGE signalling pathways RAD9, HUS1 and RAD1 form a complex (the 9-1-1 complex) that interacts wit h the RAD17-RFC2-5 complex. The 9-1-1 complex binds to the chromatin in response to DNA damage in a RAD-17-dependent manner. It has been suggested a model in which the RAD17-RFC complex recognizes DNA damage and then loads a 9-1-1 clamp around the DNA. The 9-1-1 tethers signalling and repair molecules to the DNA lesion. Consistently, although RAD17 and ATR associates independently onto chromatin, ATR-dependent RAD 17 phosphorylation requires the 9-1-1 complex, suggesting that 9-1-1 complex recruited by RAD17 enables ATR to recognize its substrates. The role, if any, of RAD17-RFC and 9-1-1 complexes in response to ICLs remains to be determined.

It has been recently reported that replication protein A (RPA) is involved in the recruitment of ATR in nuclear foci in response to IR or UV light. Moreover, RPA was found to be essential for ICLs removal, participating to lesion recognition and the subsequent endonucleolytic processing.

Our object if is to answer to three questions:
1) Are RAD17, the 9-191 complex and RPA involved in ATR activation following ICLs treatment?
2) Have RAD17, the 9-1-1 complex or RPA a role in FANC pathway activation following ICLs?
3)In what order are these proteins recruited in response to ICLs?

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CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE

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