A distinct replication fork protection pathway connects Fanconi anemia tumor suppressors to RAD51-BRCA1/2.
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.
Developmental Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. schlachk@mskcc.org
Katharina
K
Schlacher
Hong
H
Wu
Maria
M
Jasin
D024682:BRCA2 Protein / Q000235:genetics*; D002461:Cell Line, Transformed; D004261:DNA Replication; D005199:Fanconi Anemia / Q000235:genetics*; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D042822:Genomic Instability; D006801:Humans; D051135:Rad51 Recombinase / Q000378:metabolism*
D024682:BRCA2 Protein; C551750:BRCA2 protein, human; C495153:RAD51 protein, human; D051135:Rad51 Recombinase