A Distinct Replication Fork Protection Pathway Connects Fanconi Anemia Tumor Suppressors to RAD51-BRCA1/2

By K. Schlacher, Hong Wu, M. Jasin. Cancer Cell, 2012

934 citations recorded by the source corpus.

SUMMARY Genes mutated in patients with Fanconi anemia (FA) interact with the DNA repair genes BRCA1 and BRCA2/FANCD1 to suppress tumorigenesis, but the molecular functions ascribed to them cannot fully explain all of their cellular roles. Here, we show a repair-independent requirement for FA genes, including FANCD2, and BRCA1 in protecting stalled replication forks from degradation. Fork protection is surprisingly rescued in FANCD2-deficient cells by elevated RAD51 levels or stabilized RAD51 filaments. Moreover, FANCD2-mediated fork protection is epistatic with RAD51 functions, revealing an unanticipated fork protection pathway that connects FA genes to RAD51 and the BRCA1/2 breast cancer suppressors. Collective results imply a unified molecular mechanism for repair-independent functions of FA, RAD51, and BRCA1/2 proteins in preventing genomic instability and suppressing tumorigenesis.

Subfields: Molecular Biology, Plant Science

View Paper: https://www.semanticscholar.org/paper/51897ca5dd0911a925d8568e27e65a3153a7f86f

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In Molecular Biology

1. Weiran Feng
2. Yu Zhang
3. Rohit Prakash
4. M. Jasin

In Plant Science

1. M. Jasin

Citations in the corpus

• Homologous recombination and human health: the roles of BRCA1, BRCA2 and associated proteins (2015, background): “Roles for BRCA1 and canonical Fanconi anemia proteins have also been shown in nascent strand protection (Schlacher et al. 2012).”
• Identification of potentially oncogenic alterations from tumor-only samples reveals Fanconi anemia pathway mutations in bladder carcinomas (2017, background): “The FA pathway normally performs DNA repair of interstrand crosslinks, which requires homologous recombination.(44) We then assessed the overall occurrence of germline and somatic nonsense mutations in the FA pathway predicted by TOBI (Fig.”