DNA DAMAGE RESPONSE AND DNA REPLICATION

Columbia University Health Sciences, New York NY

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Abstract

Following DNA damage cells activate a multi-faceted response including cell cycle arrest and the coordinated activation of DNA repair. Failure to activate or to coordinate the DNA-damage induced signal transduction pathways can lead to chromosome breakage and loss, and to the propagation of mutations. Indeed, several cancer-prone syndromes reflect defects in the DNA damage response. These include, but are not limited to, Ataxia-Telangiectasia, Nijmegen Breakage Syndrome, Ataxia-Telangiectasia Like Disorder, Li-Fraumeni Syndrome and familial forms of breast and cervical cancers. Our long-term objective is to understand the mechanisms by which the different facets of the DNA damage response are integrated within cell cycle progression at the time of DNA replication. The ability to undergo DNA replication in the presence of DNA damage, called Radio-Resistant DNA Synthesis (RDS), is a hallmark of the cellular phenotypes of cancer-prone disorder as well as of tumor cells. We have established a cell-free system derived from Xenopus eggs that recapitulates different aspects of the DNA damage response. In particular, we have been able to identify a novel ATM- dependent cell cycle checkpoint that prevents initiation of DNA replication. We will determine whether the Xenopus homologues of Chk1 and/or Chk2/Cds1 are components of this pathway. We will also determine whether Wee1, Myt1 and/or Cdc25 are components of the pathway. We will take advantage of this cell-free system to identify which type of damages can elicit a checkpoint in vitro and whether such responses are ATM or ATR-dependent. Finally, we will examine how ATM and Mre11 complex participate in the coordinated and harmonious response to DNA damage and how cell cycle arrest is integrated with DNA repair. We anticipate that these studies will help understand some of the biochemical pathways activated by DNA damage and that, in turn; it will provide valuable information on how the DNA damage response can be impaired or lost in the case of cancer.