Role of Rad51 Paralogs in Mammalian DNA Repair

Yale University, New Haven CT

Investigators

Linked publications & trials

Abstract

Homologous recombination is an important tool for the repair of chromosomes injured by various mutagenic chemicals including alkylating agents and DNA cross-linking agents, and by ionizing radiations that cause DNA double strand breaks. The dozen or so of genes and proteins that function in concert to mediated homologous recombination are collectively referred to as the RAD52 epistasis group. Biochemical studies in this laboratory have revealed that Rad51 protein, a key member of the RAD52 group, catalyzes the formation of a heteroduplex DNA joint that links the recombining chromosomes together. Interestingly, in vertebrate cells, five Rad51-like proteins -XRCC2, XRCC3, Rad51B, Rad51C, and Rad51C- commonly called Rad51 paralogs, have been identified. These Rad51 paralogs are indispensable for efficient homologous recombination and DNA double-strand break (DSB) repair in vertebrate cells, as indicated by sensitivity of cells mutated for these paralog proteins to bifunctional DNA crosslinking agents, alkylating agents, and ionizing radiation, and by a propensity for these mutant cells to exhibit chromosomal instability. The Rad51 paralogs interact among themselves and with Rad51, however, little is known as to how they cooperate with one another, Rad51, and other RAD52 group proteins in recombination and DNA repair processes. Here, a plan is outlined to dissect the biochemical functions of the Rad51 paralogs and the role of functional domains in the Rad51 paralogs in recombination and DNA repair. The studies should shed some light on the biological functions of the Rad51 paralogs and contribute to deciphering the mechanism of homologous recombinational repair in higher eukaryotic cells.