# The expanding roles of homologous recombination proteins in genome stability

## TL;DR

This paper explores how homologous recombination proteins like RAD51 protect DNA stability beyond repair, preventing genomic instability and influencing cancer development.

## Contribution

The paper redefines homologous recombination proteins as part of an anticipatory genome-maintenance network, not just repair modules.

## Key findings

- RAD51 shields DNA from nucleolytic processing and promotes fork reversal.
- Failure to protect forks and abasic DNA in BRCA-deficient contexts accelerates genomic instability.
- HR proteins interface with base-excision repair and translesion synthesis, influencing mutational signatures in tumors.

## Abstract

Homologous recombination (HR) is traditionally portrayed as a DNA double-strand break repair pathway. However, emerging evidence positions RAD51, its partners BRCA1, BRCA2, and other HR factors at the core of a broader genome-maintenance network that operates by a “prevent and protect” strategy extending beyond repair. Here, we review how RAD51 can shield DNA from nucleolytic processing mediated by MRE11 and related nucleases, promote fork reversal, suppress replicative DNA gaps accumulation, and bind abasic sites, averting their conversion into cytotoxic intermediates. These extended functions counteract endogenous replication stress as shown in BRCA1- or BRCA2-deficient contexts, where failure to prevent gaps, protect forks, and safeguard abasic DNA accelerates genomic instability. The functional impairment of HR proteins, which interface with base-excision repair and translesion synthesis, rewires these pathways, driving distinctive base-substitution mutational signatures of HR-defective tumors. Abasic sites, especially from methyl-cytosine metabolism, put replication forks at risk of breaking, amplifying the need for RAD51-mediated defense. Such redefinition of homologous recombination protein function as part of an anticipatory surveillance and protective system, rather than a repair-only module, bears important implications for understanding tumorigenesis, therapy resistance, and aging.

Vincenzo Costanzo and coworkers review how RAD51 can shield DNA from nucleolytic processing, promote fork reversal, suppress replicative DNA gaps accumulation, and bind abasic sites to avert their conversion into cytotoxic intermediates.