Clinical PARP inhibitors do not abrogate PARP1 exchange at DNA damage sites in vivo.
Clinical PARP inhibitors do not abrogate PARP1 exchange at DNA damage sites in vivo.
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DOI：
10.1093/nar/gkaa718
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发表时间：
2020-09-25
影响因子：
14.9
通讯作者：
Zha S
中科院分区：
文献类型：
--
作者：
Shao Z;Lee BJ;Rouleau-Turcotte É;Langelier MF;Lin X;Estes VM;Pascal JM;Zha S
DNA breaks recruit and activate PARP1/2, which deposit poly-ADP-ribose (PAR) to recruit XRCC1-Ligase3 and other repair factors to promote DNA repair. Clinical PARP inhibitors (PARPi) extend the lifetime of damage-induced PARP1/2 foci, referred to as ‘trapping’. To understand the molecular nature of ‘trapping’ in cells, we employed quantitative live-cell imaging and fluorescence recovery after photo-bleaching. Unexpectedly, we found that PARP1 exchanges rapidly at DNA damage sites even in the presence of clinical PARPi, suggesting the persistent foci are not caused by physical stalling. Loss of Xrcc1, a major downstream effector of PAR, also caused persistent PARP1 foci without affecting PARP1 exchange. Thus, we propose that the persistent PARP1 foci are formed by different PARP1 molecules that are continuously recruited to and exchanging at DNA lesions due to attenuated XRCC1-LIG3 recruitment and delayed DNA repair. Moreover, mutation analyses of the NAD+ interacting residues of PARP1 showed that PARP1 can be physically trapped at DNA damage sites, and identified H862 as a potential regulator for PARP1 exchange. PARP1-H862D, but not PARylation-deficient PARP1-E988K, formed stable PARP1 foci upon activation. Together, these findings uncovered the nature of persistent PARP1 foci and identified NAD+ interacting residues involved in the PARP1 exchange.
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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
DOI：
10.1126/science.aad5168
发表时间：
2016-06-17
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Cambronne XA;Stewart ML;Kim D;Jones-Brunette AM;Morgan RK;Farrens DL;Cohen MS;Goodman RH
通讯作者：
Goodman RH
影响因子：
14.9
作者：
Hanzlikova H;Gittens W;Krejcikova K;Zeng Z;Caldecott KW
通讯作者：
Caldecott KW
DNA-PKcs 的差异磷酸化调节非同源末端连接过程中末端加工和末端连接之间的相互作用。
影响因子：
16
作者：
Jiang W;Crowe JL;Liu X;Nakajima S;Wang Y;Li C;Lee BJ;Dubois RL;Liu C;Yu X;Lan L;Zha S
通讯作者：
Zha S
影响因子：
16.6
作者：
Langelier, Marie-France;Zandarashvili, Levani;Pascal, John M.
通讯作者：
Pascal, John M.