PCAF-Mediated Histone Acetylation Promotes Replication Fork Degradation by MRE11 and EXO1 in BRCA-Deficient Cells.
PCAF-Mediated Histone Acetylation Promotes Replication Fork Degradation by MRE11 and EXO1 in BRCA-Deficient Cells.
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DOI：
10.1016/j.molcel.2020.08.018
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发表时间：
2020-10-15
期刊：
影响因子：
16
通讯作者：
Miller KM
中科院分区：
文献类型：
--
作者：
Kim JJ;Lee SY;Choi JH;Woo HG;Xhemalce B;Miller KM
停滞复制叉的稳定是BRCA缺陷肿瘤中PARP抑制剂（PARPi）耐药的一种重要机制。复制叉稳定性的表观遗传机制正在出现，但仍然知之甚少。在这里，我们报告组蛋白乙酰转移酶PCAF作为一个叉相关蛋白，促进叉降解BRCA缺陷的细胞通过乙酰化H4 K8在停滞的复制叉，招募MRE 11/EXO 1。MRE 11/EXO 1的H4 K8 ac结合结构域是它们募集到停滞的分叉所必需的。低PCAF水平，我们在BRCA 2缺陷肿瘤的子集中鉴定，稳定停滞的叉，导致BRCA缺陷细胞中的PARPi抗性。此外，PCAF活性受到ATR的严格调节，ATR使S264上的PCAF磷酸化以限制其在停滞分叉处的缔合和活性。我们的研究结果揭示了PCAF和组蛋白乙酰化是BRCA缺陷细胞中分叉稳定性和PARPi反应的关键调节因子，这为靶向BRCA缺陷肿瘤和鉴定化疗反应的表观遗传调节因子提供了关键见解。Kim等人证明了组蛋白乙酰转移酶PCAF的复制叉缔合，其促进BRCA缺陷细胞中的复制叉降解。核酸酶MRE 11和EXO 1在停滞的分叉处结合PCAF介导的H4 K8 ac。PCAF损失在BRCA缺陷细胞中赋予PARP抑制剂抗性，在化疗反应和叉稳定性中鉴定PCAF和H4 K8 ac。
Stabilization of stalled replication forks is a prominent mechanism of PARP inhibitor (PARPi) resistance in BRCA-deficient tumors. Epigenetic mechanisms of replication fork stability are emerging but remain poorly understood. Here, we report the histone acetyltransferase PCAF as a fork-associated protein that promotes fork degradation in BRCA-deficient cells by acetylating H4K8 at stalled replication forks, which recruits MRE11/EXO1. The H4K8ac binding domain of MRE11/EXO1 are required for their recruitment to stalled forks. Low PCAF levels, which we identify in a subset of BRCA2-deficient tumors, stabilize stalled forks resulting in PARPi resistance in BRCA-deficient cells. Furthermore, PCAF activity is tightly regulated by ATR, which phosphorylates PCAF on S264 to limit its association and activity at stalled forks. Our results reveal PCAF and histone acetylation as critical regulators of fork stability and PARPi responses in BRCA-deficient cells, which provides key insights into targeting BRCA-deficient tumors and identifying epigenetic modulators of chemotherapeutic responses. Kim et al. demonstrate replication fork association of the histone acetyltransferase PCAF, which promotes replication fork degradation in BRCA-deficient cells. Nucleases MRE11 and EXO1 bind PCAF-mediated H4K8ac at stalled forks. PCAF loss confers PARP inhibitor resistance in BRCA-deficient cells, identifying PCAF and H4K8ac in chemotherapeutic responses and fork stability.
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DOI：
10.1038/nrc2644
发表时间：
2009-06
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.8
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
通讯作者：
Nussenzweig A
影响因子：
64.5
作者：
Fekairi S;Scaglione S;Chahwan C;Taylor ER;Tissier A;Coulon S;Dong MQ;Ruse C;Yates JR 3rd;Russell P;Fuchs RP;McGowan CH;Gaillard PHL
通讯作者：
Gaillard PHL
DOI：
10.1007/978-1-4939-1680-1_10
发表时间：
2015
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Dungrawala, Huzefa;Cortez, David
通讯作者：
Cortez, David
影响因子：
10.5
作者：
Bansbach, Carol E.;Betous, Remy;Cortez, David
通讯作者：
Cortez, David