BRCA1 recruitment to transcriptional pause sites is required for R-loop-driven DNA damage repair.
BRCA1 recruitment to transcriptional pause sites is required for R-loop-driven DNA damage repair.
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DOI：
10.1016/j.molcel.2015.01.011
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发表时间：
2015-02-19
期刊：
影响因子：
16
通讯作者：
Livingston, David M.
中科院分区：
文献类型：
--
作者：
Hatchi, Elodie;Skourti-Stathaki, Konstantina;Ventz, Steffen;Pinello, Luca;Yen, Angela;Kamieniarz-Gdula, Kinga;Dimitrov, Stoil;Pathania, Shailja;McKinney, Kristine M.;Eaton, Matthew L.;Kellis, Manolis;Hill, Sarah J.;Parmigiani, Giovanni;Proudfoot, Nicholas J.;Livingston, David M.
导致转录相关基因组不稳定的机制既复杂又不完全清楚。虽然R-环是正常的转录中间产物，但它们也与基因组的不稳定性有关。在这里，我们证明了BRCA1被招募到通常在转录终止区的子集上形成的R-环。在那里，它调节一个特定的生理结合伙伴--Senataxin(SETX)的招募。这个复合体的破坏导致了R环驱动的DNA损伤，这反映在相邻的γ-H2AX积累和相关R环结构的非转录链中的单链DNA断裂。全基因组分析显示，在活跃转录基因的富含R环的终止区(TRs)，BRCA1结合广泛丰富。值得注意的是，在BRCA1缺失的乳腺肿瘤中的一些基因中，存在特定的插入/缺失突变，位于TRs内接近R环介导的BRCA1结合位点的位置。因此，BRCA1/SETX复合体支持一种DNA修复机制，该机制解决了转录暂停位点基于R环的DNA损伤。内源性BRCA1和SETX在BRCA1驱动的过程中相互作用BRCA1/SETX复合体被招募到R环相关终止区(TRs)BRCA1/SETX复合体抑制附近R环产生的转录DNA损伤BRCA1乳腺癌在BRCA1受体结合区附近发生内部突变转录R环对基因组完整性构成潜在威胁。Hatchi等人。结果表明，BRCA1与SETX合作，参与了一种DNA修复机制，该机制处理R-环相关的基因组在转录终止暂停位点的不稳定性。
The mechanisms contributing to transcription-associated genomic instability are both complex and incompletely understood. Although R-loops are normal transcriptional intermediates, they are also associated with genomic instability. Here, we show that BRCA1 is recruited to R-loops that form normally over a subset of transcription termination regions. There it mediates the recruitment of a specific, physiological binding partner, senataxin (SETX). Disruption of this complex led to R-loop-driven DNA damage at those loci as reflected by adjacent γ-H2AX accumulation and ssDNA breaks within the untranscribed strand of relevant R-loop structures. Genome-wide analysis revealed widespread BRCA1 binding enrichment at R-loop-rich termination regions (TRs) of actively transcribed genes. Strikingly, within some of these genes in BRCA1 null breast tumors, there are specific insertion/deletion mutations located close to R-loop-mediated BRCA1 binding sites within TRs. Thus, BRCA1/SETX complexes support a DNA repair mechanism that addresses R-loop-based DNA damage at transcriptional pause sites. Endogenous BRCA1 and senataxin (SETX) interact in a BRCA1-driven process BRCA1/SETX complexes are recruited to R-loop-associated termination regions (TRs) BRCA1/SETX complexes suppress transcriptional DNA damage arising at nearby R-loops BRCA1 breast cancers reveal indel mutations near BRCA1 TR binding regions Transcriptional R-loops represent a potential threat to genome integrity. Hatchi et al. show that BRCA1, in partnership with SETX, is engaged in a DNA repair mechanism that deals with R-loop-associated genomic instability at transcriptional termination pause sites.
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影响因子：
10.5
作者：
Davidson L;Muniz L;West S
通讯作者：
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影响因子：
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作者：
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发表时间：
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期刊：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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