FANCD2 Maintains Fork Stability in BRCA1/2-Deficient Tumors and Promotes Alternative End-Joining DNA Repair

被引：152

作者：

Kais, Zeina ^{[1
]}

Rondinelli, Beatrice ^{[1
]}

Holmes, Amie ^{[1
]}

O'Leary, Colin ^{[1
]}

Kozono, David ^{[1
]}

D'Andrea, Alan D. ^{[1
,2
]}

Ceccaldi, Raphael ^{[1
]}

机构：

[1] Harvard Univ, Dana Farber Canc Inst, Dept Radiat Oncol, Sch Med, Boston, MA 02215 USA

[2] Dana Farber Canc Inst, Ctr DNA Damage & Repair, Boston, MA 02215 USA

来源：

CELL REPORTS | 2016年 / 15卷 / 11期

关键词：

FANCONI-ANEMIA PATHWAY; DOUBLE-STRAND BREAKS; CROSS-LINK REPAIR; REPLICATION FORKS; HOMOLOGOUS-RECOMBINATION; MONOUBIQUITINATED FANCD2; GENOMIC INSTABILITY; S PHASE; BRCA1; CTIP;

D O I：

10.1016/j.celrep.2016.05.031

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

BRCA1/2 proteins function in homologous recombination (HR)-mediated DNA repair and cooperate with Fanconi anemia (FA) proteins to maintain genomic integrity through replication fork stabilization. Loss of BRCA1/2 proteins results in DNA repair deficiency and replicative stress, leading to genomic instability and enhanced sensitivity to DNA-damaging agents. Recent studies have shown that BRCA1/2deficient tumors upregulate Polq-mediated alternative end-joining (alt-EJ) repair as a survival mechanism. Whether other mechanisms maintain genomic integrity upon loss of BRCA1/2 proteins is currently unknown. Here we show that BRCA1/2-deficient tumors also upregulate FANCD2 activity. FANCD2 is required for fork protection and fork restart in BRCA1/2-deficient tumors. Moreover, FANCD2 promotes Polq recruitment at sites of damage and altEJ repair. Finally, loss of FANCD2 in BRCA1/2-deficient tumors enhances cell death. These results reveal a synthetic lethal relationship between FANCD2 and BRCA1/2, and they identify FANCD2 as a central player orchestrating DNA repair pathway choice at the replication fork.

引用

页码：2488 / 2499

页数：12

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