Non-Recombinogenic Functions of Rad51, BRCA2, and Rad52 in DNA Damage Tolerance.

Félix Prado

doi:10.3390/genes12101550

Abstract

The DNA damage tolerance (DDT) response is aimed to timely and safely complete DNA replication by facilitating the advance of replication forks through blocking lesions. This process is associated with an accumulation of single-strand DNA (ssDNA), both at the fork and behind the fork. Lesion bypass and ssDNA filling can be performed by translation synthesis (TLS) and template switching mechanisms. TLS uses low-fidelity polymerases to incorporate a dNTP opposite the blocking lesion, whereas template switching uses a Rad51/ssDNA nucleofilament and the sister chromatid to bypass the lesion. Rad51 is loaded at this nucleofilament by two mediator proteins, BRCA2 and Rad52, and these three factors are critical for homologous recombination (HR). Here, we review recent advances showing that Rad51, BRCA2, and Rad52 perform some of these functions through mechanisms that do not require the strand exchange activity of Rad51: the formation and protection of reversed fork structures aimed to bypass blocking lesions, and the promotion of TLS. These findings point to the central HR proteins as potential molecular switches in the choice of the mechanism of DDT.

Highlights

Homologous recombination (HR) mechanisms repair DNA breaks using intact homologous DNA sequences as template
The role of Rad51, BRCA2, and Rad52 in DNA damage tolerance (DDT) was restricted to HR mechanisms
A major conclusion of these results is that Rad51 and its mediators take part in most DDT mechanisms, and they become a potential molecular switch to decide how to tolerate the lesion at different stages

Summary

Introduction

Homologous recombination (HR) mechanisms repair DNA breaks using intact homologous DNA sequences as template (donor molecule). The search for homology and strand exchange are central molecular steps for HR mechanisms associated with both double-strand break (DSB) repair and single-strand DNA (ssDNA) filling. These steps are carried out by a ssDNA molecule coated with the Rad protein (RecA in bacteria), which is the central protein in HR. 2. DSB Repair by HR Most of our knowledge about the mechanisms and factors involved in HR comes from the study of DSB repair both in mitosis and meiosis, where the recombinational repair of programmed DSBs is critical for the formation of viable meiotic products.

DSB Repair by HR

Non-Recombinogenic Roles of Rad51 and Rad52 in TLS

Concluding Remarks