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<p>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.</p>

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The expanding roles of homologous recombination proteins in genome stability

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月3日

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  • Lorenzo Sassi,
  • Andrea Martinez Marroquin,
  • Salli Waked,
  • Alessandra Ardizzoia,
  • Vincenzo Costanzo

摘要

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.