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DNA damage response


Principal Investigator: Dea Slade

DNA damage response (DDR) is a complex regulatory network that involves DNA damage sensing, signalling and repair. These processes are carried out by diverse enzymatic activities that must be precisely co-ordinated as to ensure the efficient, accurate and timely repair of DNA damage and the preservation of genomic integrity. The dynamics of the DDR protein network is governed by post-translational modifications including phosphorylation, methylation, acetylation, ubiquitination, sumoylation and poly(ADP-ribosyl)ation (PARylation). They regulate the recruitment of DNA repair factors to the sites of DNA damage, their enzymatic activity, interactions and the choice of the DNA repair pathway. Our research focuses on the regulation of DDR by reversible PARylation and acetylation modifications.

Poly(ADP-ribose) (PAR) is rapidly produced in response to DNA damage by PARP polymerases and elicits the recruitment of different DDR factors to DNA damage sites. PAR is rapidly degraded by the PARG glycosylase to ensure a transient effect. While PAR is the largest post-translational protein modification, acetylation is the most prevalent. Among numerous deacetylases, in recent years sirtuins (SIRTs) have emerged as crucial regulators of gene expression, metabolism and genome integrity that interconnect with the PAR processes. As NAD-consuming enzymes, PARPs and sirtuins are activated in conditions of genotoxic, oxidative, metabolic and inflammatory stress, which alter NAD levels. They regulate cellular response to stress through changes in chromatin structure, gene expression, DNA repair, cell cycle, metabolism and cell fate.

Among 17 PARP family members and seven sirtuins in mammals, PARP1, PARP2, PARP3, SIRT1, and SIRT6 are hitherto known to affect DDR. PARP1/2 and SIRT1 deficiencies sensitize the cells to DNA-damaging agents and result in embryonic lethality due to genomic instability. However, little is known about DNA repair processes regulated by sirtuins and the relationship between sirtuin- and PARP-mediated modifications of DNA repair proteins. The observations that PARPs and sirtuins regulate each other’s levels and activities and have opposite effects on the same pathway such as cell death suggest a functional interplay between these NAD-consuming enzyme families.

Our aim is to identify unknown DDR protein targets regulated by PARPs and sirtuins and characterize their functional interplay by using biochemical and cell biological techniques in mammalian systems. This line of research is intended to improve our understanding of how PARPs and sirtuins preserve genomic stability, which is compromised in cancer and aging. The findings that PARP1 inhibitors are extremely efficient in the treatment of BRCA-mutated breast cancer and that sirtuins extend healthspan and lifespan attest to their therapeutic importance. Identification of physiological sirtuin substrates will enable the design of substrate-specific modulators of sirtuin activity, which, like PARP inhibitors, have a potential application for the treatment of cancer and age-related diseases.