FANCD2 Maintains Fork Stability in BRCA1/2-Deficient Tumors and Promotes Alternative End-Joining DNA Repair.
FANCD2 Maintains Fork Stability in BRCA1/2-Deficient Tumors and Promotes Alternative End-Joining DNA Repair.
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DOI：
10.1016/j.celrep.2016.05.031
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发表时间：
2016-06-14
期刊：
影响因子：
8.8
通讯作者：
Ceccaldi R
中科院分区：
文献类型：
--
作者：
Kais Z;Rondinelli B;Holmes A;O'Leary C;Kozono D;D'Andrea AD;Ceccaldi R
BRCA1/2蛋白在同源重组（HR）介导的DNA修复中发挥作用，并与范可尼贫血（FA）蛋白协同通过稳定复制叉来维持基因组完整性。BRCA1/2蛋白的缺失导致DNA修复缺陷和复制应激，进而引起基因组不稳定以及对DNA损伤剂的敏感性增强。近期研究表明，BRCA1/2缺陷型肿瘤会上调Polθ介导的替代性末端连接（alt - EJ）修复作为一种生存机制。在BRCA1/2蛋白缺失的情况下是否有其他机制维持基因组完整性目前尚不清楚。在此我们表明，BRCA1/2缺陷型肿瘤还会上调FANCD2的活性。在BRCA1/2缺陷型肿瘤中，FANCD2对于复制叉保护和复制叉重启是必需的。此外，FANCD2促进Polθ在损伤位点的募集以及alt - EJ修复。最后，在BRCA1/2缺陷型肿瘤中FANCD2的缺失会增强细胞死亡。这些结果揭示了FANCD2和BRCA1/2之间存在一种合成致死关系，并确定FANCD2是在复制叉处协调DNA修复途径选择的核心参与者。
凯斯等人表明，BRCA1/2缺陷型肿瘤中FANCD2活性有代偿性增加。FANCD2在BRCA1/2缺陷型肿瘤中稳定停滞的复制叉并促进替代性末端连接（alt - EJ）。在这些肿瘤中FANCD2的缺失导致严重的DNA修复缺陷以及细胞死亡增加。
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 BRCA1/2-deficient tumors upregulate Polθ-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 Polθ recruitment at sites of damage and alt-EJ 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 identify FANCD2 as a central player orchestrating DNA repair pathway choice at the replication fork. Kais et al. show that BRCA1/2-deficient tumors have a compensatory increase in FANCD2 activity. FANCD2 stabilizes stalled replication forks and promotes alternative end-joining (alt-EJ) in BRCA1/2-deficient tumors. Loss of FANCD2 in these tumors results in severe DNA repair defects and enhanced cell death.