Regulation of ALT-associated homology-directed repair by polyADP-ribosylation.
Regulation of ALT-associated homology-directed repair by polyADP-ribosylation.
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通过聚ADP-核糖基化调节ALT相关同源定向修复。
DOI：
10.1038/s41594-020-0512-7
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发表时间：
2020-12
影响因子：
16.8
通讯作者：
O'Sullivan RJ
中科院分区：
文献类型：
--
作者：
Hoang SM;Kaminski N;Bhargava R;Barroso-González J;Lynskey ML;García-Expósito L;Roncaioli JL;Wondisford AR;Wallace CT;Watkins SC;James DI;Waddell ID;Ogilvie D;Smith KM;da Veiga Leprevost F;Mellacharevu D;Nesvizhskii AI;Li J;Ray-Gallet D;Sobol RW;Almouzni G;O'Sullivan RJ
聚adp核糖（PAR）的合成重新配置了局部染色质环境，并向受损的染色质招募dna修复复合物。聚（adp -核糖）糖水解酶（PARG）降解PAR对DNA修复的进展和完成至关重要。在这里，我们表明抑制PARG破坏同源定向修复（HDR）机制，该机制支持端粒的选择性延长（ALT）。蛋白质组学分析揭示了ALT癌细胞中聚（adp -核糖基）化（PARylation）在调节染色质组装因子HIRA中的新作用。我们发现HIRA在G2期在端粒富集，是组蛋白H3.3沉积和端粒DNA合成所必需的。HIRA的缺失引起ALT癌细胞的全身性死亡，这种死亡可以通过ATRX的重新表达来减轻，ATRX是ALT肿瘤中经常失活的一种蛋白质。我们认为PARylation使HIRA在对ALT癌症中普遍存在的ATRX缺乏的适应性反应中发挥其重要作用。
The synthesis of poly(ADP-ribose) (PAR) reconfigures the local chromatin environment and recruits DNA-repair complexes to damaged chromatin. PAR degradation by poly(ADP-ribose) glycohydrolase (PARG) is essential for progression and completion of DNA repair. Here, we show that inhibition of PARG disrupts homology-directed repair (HDR) mechanisms that underpin alternative lengthening of telomeres (ALT). Proteomic analyses uncover a new role for poly(ADP-ribosyl)ation (PARylation) in regulating the chromatin-assembly factor HIRA in ALT cancer cells. We show that HIRA is enriched at telomeres during the G2 phase and is required for histone H3.3 deposition and telomere DNA synthesis. Depletion of HIRA elicits systemic death of ALT cancer cells that is mitigated by re-expression of ATRX, a protein that is frequently inactivated in ALT tumors. We propose that PARylation enables HIRA to fulfill its essential role in the adaptive response to ATRX deficiency that pervades ALT cancers.
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影响因子：
8.8
作者：
Garcia-Exposito L;Bournique E;Bergoglio V;Bose A;Barroso-Gonzalez J;Zhang S;Roncaioli JL;Lee M;Wallace CT;Watkins SC;Opresko PL;Hoffmann JS;O'Sullivan RJ
通讯作者：
O'Sullivan RJ
影响因子：
14.9
作者：
Gagné JP;Pic E;Isabelle M;Krietsch J;Ethier C;Paquet E;Kelly I;Boutin M;Moon KM;Foster LJ;Poirier GG
通讯作者：
Poirier GG
影响因子：
64.5
作者：
Goldberg AD;Banaszynski LA;Noh KM;Lewis PW;Elsaesser SJ;Stadler S;Dewell S;Law M;Guo X;Li X;Wen D;Chapgier A;DeKelver RC;Miller JC;Lee YL;Boydston EA;Holmes MC;Gregory PD;Greally JM;Rafii S;Yang C;Scambler PJ;Garrick D;Gibbons RJ;Higgs DR;Cristea IM;Urnov FD;Zheng D;Allis CD
通讯作者：
Allis CD
影响因子：
16.8
作者：
Berti, Matteo;Chaudhuri, Arnab Ray;Thangavel, Saravanabhavan;Gomathinayagam, Shivasankari;Kenig, Sasa;Vujanovic, Marko;Odreman, Federico;Glatter, Timo;Graziano, Simona;Mendoza-Maldonado, Ramiro;Marino, Francesca;Lucic, Bojana;Biasin, Valentina;Gstaiger, Matthias;Aebersold, Ruedi;Sidorova, Julia M.;Monnat, Raymond J., Jr.;Lopes, Massimo;Vindigni, Alessandro
通讯作者：
Vindigni, Alessandro
影响因子：
14.9
作者：
Illuzzi G;Fouquerel E;Amé JC;Noll A;Rehmet K;Nasheuer HP;Dantzer F;Schreiber V
通讯作者：
Schreiber V