Requirement for PBAF in transcriptional repression and repair at DNA breaks in actively transcribed regions of chromatin.
Requirement for PBAF in transcriptional repression and repair at DNA breaks in actively transcribed regions of chromatin.
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DOI：
10.1016/j.molcel.2014.06.028
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发表时间：
2014-09-04
期刊：
影响因子：
16
通讯作者：
Downs, Jessica A.
中科院分区：
文献类型：
--
作者：
Kakarougkas, Andreas;Ismail, Amani;Chambers, Anna L.;Riballo, Enriqueta;Herbert, Alex D.;Kuenzel, Julia;Loebrich, Markus;Jeggo, Penny A.;Downs, Jessica A.
基因组的活跃转录区域容易受到基因组不稳定的影响。最近，人们发现转录受到邻近 DNA 双链断裂 (DSB) 的抑制。目前尚不清楚侧翼 DSB 转录失败是否会对 DNA 修复效率产生任何影响，也不知道染色质重塑剂是否对该过程有所贡献。在这里，我们表明，PBAF 重塑复合物对于 DSB 诱导的转录沉默非常重要，并促进早期时间点 DNA DSB 子集的修复，这可以通过全局抑制转录来挽救。这两个过程都需要 BAF180（PBAF 亚基）上的 ATM 磷酸化位点。此外，我们发现 PRC1 和 PRC2 多梳基复合物的亚基对于 DSB 诱导的沉默和促进修复也同样需要。癌症相关的 BAF180 突变体无法恢复这些功能，这表明 PBAF 在抑制 DSB 附近转录中的作用可能有助于其肿瘤抑制活性。 BAF180 有助于双链断裂 (DSB) 诱导的转录沉默 转录活性 DSB 依赖于 BAF180 来有效修复 PcG 复合物，并且这些活动需要 BAF180 的 ATM 磷酸化 癌症相关的 BAF180 突变体无法恢复这些功能 细胞响应邻近 DNA 双链断裂而沉默正在进行的转录。卡卡罗卡斯等人。表明 PBAF 染色质重塑复合物对于这一事件很重要，并且未能沉默转录会导致修复延迟。
Actively transcribed regions of the genome are vulnerable to genomic instability. Recently, it was discovered that transcription is repressed in response to neighboring DNA double-strand breaks (DSBs). It is not known whether a failure to silence transcription flanking DSBs has any impact on DNA repair efficiency or whether chromatin remodelers contribute to the process. Here, we show that the PBAF remodeling complex is important for DSB-induced transcriptional silencing and promotes repair of a subset of DNA DSBs at early time points, which can be rescued by inhibiting transcription globally. An ATM phosphorylation site on BAF180, a PBAF subunit, is required for both processes. Furthermore, we find that subunits of the PRC1 and PRC2 polycomb group complexes are similarly required for DSB-induced silencing and promoting repair. Cancer-associated BAF180 mutants are unable to restore these functions, suggesting PBAF's role in repressing transcription near DSBs may contribute to its tumor suppressor activity. BAF180 contributes to double-strand break (DSB)-induced transcriptional silencing Transcriptionally active DSBs are dependent on BAF180 for efficient repair PcG complexes and ATM phosphorylation of BAF180 are required for these activities Cancer-associated BAF180 mutants are unable to restore these functions Cells silence ongoing transcription in response to a neighboring DNA double-strand break. Kakarougkas et al. show that the PBAF chromatin remodeling complex is important for this event and that failure to silence transcription leads to a delay in repair.
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影响因子：
11.2
作者：
Stiff, T;O'Driscoll, M;Jeggo, PA
通讯作者：
Jeggo, PA
DOI：
10.1038/nrg3345
发表时间：
2013-01
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.8
作者：
Varela, Ignacio;Tarpey, Patrick;Raine, Keiran;Huang, Dachuan;Ong, Choon Kiat;Stephens, Philip;Davies, Helen;Jones, David;Lin, Meng-Lay;Teague, Jon;Bignell, Graham;Butler, Adam;Cho, Juok;Dalgliesh, Gillian L.;Galappaththige, Danushka;Greenman, Chris;Hardy, Claire;Jia, Mingming;Latimer, Calli;Lau, King Wai;Marshall, John;McLaren, Stuart;Menzies, Andrew;Mudie, Laura;Stebbings, Lucy;Largaespada, David A.;Wessels, L. F. A.;Richard, Stephane;Kahnoski, Richard J.;Anema, John;Tuveson, David A.;Perez-Mancera, Pedro A.;Mustonen, Ville;Fischer, Andrej;Adams, David J.;Rust, Alistair;Chan-on, Waraporn;Subimerb, Chutima;Dykema, Karl;Furge, Kyle;Campbell, Peter J.;Teh, Bin Tean;Stratton, Michael R.;Futreal, P. Andrew
通讯作者：
Futreal, P. Andrew
影响因子：
64.5
作者：
Shanbhag NM;Rafalska-Metcalf IU;Balane-Bolivar C;Janicki SM;Greenberg RA
通讯作者：
Greenberg RA
影响因子：
21.3
作者：
Noon, Angela T.;Shibata, Atsushi;Goodarzi, Aaron A.
通讯作者：
Goodarzi, Aaron A.