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

被引：736

作者：

Schlacher, Katharina ^{[1
,2
]}

Wu, Hong ^{[2
,3
]}

Jasin, Maria ^{[1
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Dev Biol Program, New York, NY 10065 USA

[2] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA

[3] Univ Calif Los Angeles, Inst Mol Med, Los Angeles, CA 90095 USA

来源：

CANCER CELL | 2012年 / 22卷 / 01期

关键词：

CROSS-LINK REPAIR; STRAND-BREAK REPAIR; DNA-DAMAGE; BLOOMS-SYNDROME; CELLS; CANCER; PROTEIN; GENOME; FANCD2; BRCA2;

D O I：

10.1016/j.ccr.2012.05.015

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：106 / 116

页数：11

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