H3K4 methylation by SETD1A/BOD1L facilitates RIF1-dependent NHEJ.
H3K4 methylation by SETD1A/BOD1L facilitates RIF1-dependent NHEJ.
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DOI：
10.1016/j.molcel.2022.03.030
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发表时间：
2022-05-19
期刊：
影响因子：
16
通讯作者：
Higgs, Martin R.
中科院分区：
文献类型：
--
作者：
Bayley, Rachel;Borel, Valerie;Moss, Rhiannon J.;Sweatman, Ellie;Ruis, Philip;Ormrod, Alice;Goula, Amalia;Mottram, Rachel M. A.;Stanage, Tyler;Hewitt, Graeme;Saponaro, Marco;Stewart, Grant S.;Boulton, Simon J.;Higgs, Martin R.
53bp1 - rif1 -屏蔽蛋白通路通过抑制DNA双链断裂（DSBs）末端的核分解降解来维持基因组的稳定性。尽管RIF1通过phospho-53BP1与受损的染色质相互作用，并促进屏蔽蛋白复合物向dsb的募集，但尚不清楚是否有其他调控线索参与了这种反应。在这里，我们暗示SETD1A-BOD1L在赖氨酸4处的组蛋白H3甲基化参与了RIF1向dsb的募集。SETD1A或BOD1L表达的降低或H3K4甲基化的失调会导致DNA末端不受控制的切除，损害功能失调端粒的末端连接，并取消类开关重组。此外，在携带SETD1A功能丧失突变的患者细胞中，RIF1定位到dsb的缺陷是明显的。在brca1缺陷细胞中，setd1a依赖性RIF1募集的缺失恢复了同源重组，并导致对聚（adp -核糖）聚合酶抑制的抗性，从而加强了这些观察结果的临床相关性。在机制上，RIF1直接与甲基化的H3K4结合，促进其招募到dsb或稳定在dsb上。BOD1L、SET1A和H3K4me3促进RIF1在DNA断裂位点的积累SETD1A依赖的H3K4甲基化促进末端连接和抑制末端切除干扰SETD1A使brca1缺陷细胞对PARP抑制剂产生抗性，RIF1直接结合甲基化的H3K4 Bayley等人发现SETD1A通过促进RIF1在受损位点的积累，对DNA修复至关重要。H3甲基化或SETD1A-BOD1L复合物的缺陷会损害断裂DNA末端的末端连接，取消类开关重组，促进不受控制的末端切除，并影响PARP抑制剂的功效。
The 53BP1-RIF1-shieldin pathway maintains genome stability by suppressing nucleolytic degradation of DNA ends at double-strand breaks (DSBs). Although RIF1 interacts with damaged chromatin via phospho-53BP1 and facilitates recruitment of the shieldin complex to DSBs, it is unclear whether other regulatory cues contribute to this response. Here, we implicate methylation of histone H3 at lysine 4 by SETD1A-BOD1L in the recruitment of RIF1 to DSBs. Compromising SETD1A or BOD1L expression or deregulating H3K4 methylation allows uncontrolled resection of DNA ends, impairs end-joining of dysfunctional telomeres, and abrogates class switch recombination. Moreover, defects in RIF1 localization to DSBs are evident in patient cells bearing loss-of-function mutations in SETD1A. Loss of SETD1A-dependent RIF1 recruitment in BRCA1-deficient cells restores homologous recombination and leads to resistance to poly(ADP-ribose)polymerase inhibition, reinforcing the clinical relevance of these observations. Mechanistically, RIF1 binds directly to methylated H3K4, facilitating its recruitment to, or stabilization at, DSBs. BOD1L, SET1A, and H3K4me3 promote RIF1 accumulation at DNA break sites SETD1A-dependent H3K4 methylation promotes end-joining and suppresses end-resection Perturbing SETD1A confers resistance to PARP inhibitors in BRCA1-deficient cells RIF1 binds directly to methylated H3K4 Bayley et al. identify histone H3K4 methylation by SETD1A as vital for DNA repair, by promoting RIF1 accumulation at damaged sites. Deficiencies in H3 methylation or the SETD1A-BOD1L complex impairs end-joining of broken DNA ends, abrogates class switch recombination, promotes uncontrolled end-resection, and compromises the efficacy of PARP inhibitors.
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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：
16
作者：
Foti R;Gnan S;Cornacchia D;Dileep V;Bulut-Karslioglu A;Diehl S;Buness A;Klein FA;Huber W;Johnstone E;Loos R;Bertone P;Gilbert DM;Manke T;Jenuwein T;Buonomo SC
通讯作者：
Buonomo SC
由 53BP1-RIF1 和 BRCA1-CtIP 组成的细胞周期依赖性调节回路控制 DNA 修复途径的选择。
影响因子：
16
作者：
Escribano-Diaz, Cristina;Orthwein, Alexandre;Durocher, Daniel
通讯作者：
Durocher, Daniel
影响因子：
64.5
作者：
Hoshii T;Cifani P;Feng Z;Huang CH;Koche R;Chen CW;Delaney CD;Lowe SW;Kentsis A;Armstrong SA
通讯作者：
Armstrong SA
影响因子：
21.3
作者：
Dev H;Chiang TW;Lescale C;de Krijger I;Martin AG;Pilger D;Coates J;Sczaniecka-Clift M;Wei W;Ostermaier M;Herzog M;Lam J;Shea A;Demir M;Wu Q;Yang F;Fu B;Lai Z;Balmus G;Belotserkovskaya R;Serra V;O'Connor MJ;Bruna A;Beli P;Pellegrini L;Caldas C;Deriano L;Jacobs JJL;Galanty Y;Jackson SP
通讯作者：
Jackson SP