Replication fork stability confers chemoresistance in BRCA-deficient cells.
Replication fork stability confers chemoresistance in BRCA-deficient cells.
复制标题
DOI：
10.1038/nature18325
复制
发表时间：
2016-07-21
期刊：
影响因子：
64.8
通讯作者：
Nussenzweig A
中科院分区：
文献类型：
--
作者：
Ray Chaudhuri A;Callen E;Ding X;Gogola E;Duarte AA;Lee JE;Wong N;Lafarga V;Calvo JA;Panzarino NJ;John S;Day A;Crespo AV;Shen B;Starnes LM;de Ruiter JR;Daniel JA;Konstantinopoulos PA;Cortez D;Cantor SB;Fernandez-Capetillo O;Ge K;Jonkers J;Rottenberg S;Sharan SK;Nussenzweig A
BRCA1和BRCA2缺陷细胞通过同源重组(HR)修复DNA双链断裂(DSB)的能力降低，因此对DNA损伤剂，包括顺铂和多聚(ADP-核糖)聚合酶(PARP)抑制剂高度敏感。在这里，我们表明，丢失MLL3/4复合蛋白PTIP，保护BRCA1/2缺陷细胞免受DNA损伤，并挽救BRCA2缺陷胚胎干细胞的致命性。然而，PTIP缺乏并不能恢复DSB的HR活动。相反，它的缺乏抑制了Mre11核酸酶在停滞不前的复制叉上的招募，这反过来又保护了新生的DNA链免受广泛降解。更广泛地说，获得PARPI和顺铂耐药性与BRCA2缺陷性肿瘤细胞的复制分叉(RF)保护有关，这些肿瘤细胞不会发生BRCA2逆转突变。包括PARP1和CHD4在内的多个蛋白质的破坏导致了相同的RF保护终点，突显了肿瘤细胞逃避化疗干预和获得耐药性的复杂性。
Brca1- and Brca2-deficient cells have reduced capacity to repair DNA double-strand breaks (DSBs) by homologous recombination (HR) and consequently are hypersensitive to DNA damaging agents, including cisplatin and poly(ADP-ribose) polymerase (PARP) inhibitors. Here we show that loss of the MLL3/4 complex protein, PTIP, protects Brca1/2-deficient cells from DNA damage and rescues the lethality of Brca2-deficient embryonic stem cells. However, PTIP deficiency does not restore HR activity at DSBs. Instead, its absence inhibits the recruitment of the MRE11 nuclease to stalled replication forks, which in turn protects nascent DNA strands from extensive degradation. More generally, acquisition of PARPi and cisplatin resistance is associated with replication fork (RF) protection in Brca2-deficient tumor cells that do not develop Brca2 reversion mutations. Disruption of multiple proteins, including PARP1 and CHD4, leads to the same end point of RF protection, highlighting the complexities by which tumor cells evade chemotherapeutic interventions and acquire drug resistance.