A localized nucleolar DNA damage response facilitates recruitment of the homology-directed repair machinery independent of cell cycle stage.
A localized nucleolar DNA damage response facilitates recruitment of the homology-directed repair machinery independent of cell cycle stage.
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DOI：
10.1101/gad.260703.115
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发表时间：
2015-06-01
影响因子：
10.5
通讯作者：
McStay B
中科院分区：
文献类型：
--
作者：
van Sluis M;McStay B
DNA修复途径的选择被认为是由细胞周期时间和染色质环境决定的。van Sluis等人发现，定向地将双链断裂（DSBs）引入rDNA，而不是相邻序列，导致RNA聚合酶对其转录的atm依赖性抑制。重要的是，rDNA内的DSBs在整个细胞周期内招募同源重组机制。DNA双链断裂的修复主要有两种途径：非同源末端连接（non - homologous end-joining）和同源重组（homologous recombination， HR）。修复途径的选择被认为是由细胞周期时间和染色质环境决定的。核仁是核糖体生物发生的重要核亚结构域和位点，形成于核仁组织者区（NORs）周围，NORs包含位于人类顶中心染色体p臂上的rDNA阵列。主动转录的rDNA重复序列位于核仁内部，而NORs的近端和远端序列被包装为位于核仁外围的异染色质。NORs提供了一个机会来研究DSB在高度转录、重复和基本位点上的反应。有针对性地将dsb引入rDNA，而不是邻近序列，导致RNA聚合酶i对其转录的atm依赖性抑制。这与rDNA从核核内部移动到外围的锚定点相结合。重组使rDNA能够接近通常排除在核仁之外的修复因子。重要的是，rDNA内的dsb在整个细胞周期内招募HR机制。此外，在G1细胞中可以观察到非预定的DNA合成，与受损NORs的HR一致。这些结果表明，HR可以在cis中被模板化，并提示染色体背景在维持NOR基因组稳定性中的作用。
DNA repair pathway choice is thought to be determined by cell cycle timing and chromatin context. van Sluis et al. find that targeted introduction of double-strand breaks (DSBs) into rDNA, but not abutting sequences, results in ATM-dependent inhibition of their transcription by RNA polymerase I. Importantly, DSBs within rDNA recruit the homologous recombination machinery throughout the cell cycle. DNA double-strand breaks (DSBs) are repaired by two main pathways: nonhomologous end-joining and homologous recombination (HR). Repair pathway choice is thought to be determined by cell cycle timing and chromatin context. Nucleoli, prominent nuclear subdomains and sites of ribosome biogenesis, form around nucleolar organizer regions (NORs) that contain rDNA arrays located on human acrocentric chromosome p-arms. Actively transcribed rDNA repeats are positioned within the interior of the nucleolus, whereas sequences proximal and distal to NORs are packaged as heterochromatin located at the nucleolar periphery. NORs provide an opportunity to investigate the DSB response at highly transcribed, repetitive, and essential loci. Targeted introduction of DSBs into rDNA, but not abutting sequences, results in ATM-dependent inhibition of their transcription by RNA polymerase I. This is coupled with movement of rDNA from the nucleolar interior to anchoring points at the periphery. Reorganization renders rDNA accessible to repair factors normally excluded from nucleoli. Importantly, DSBs within rDNA recruit the HR machinery throughout the cell cycle. Additionally, unscheduled DNA synthesis, consistent with HR at damaged NORs, can be observed in G1 cells. These results suggest that HR can be templated in cis and suggest a role for chromosomal context in the maintenance of NOR genomic stability.
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影响因子：
11.4
作者：
Aylon, Y;Liefshitz, B;Kupiec, M
通讯作者：
Kupiec, M
影响因子：
14.9
作者：
Eklund JL;Ulge UY;Eastberg J;Monnat RJ Jr
通讯作者：
Monnat RJ Jr
影响因子：
7
作者：
Floutsakou I;Agrawal S;Nguyen TT;Seoighe C;Ganley AR;McStay B
通讯作者：
McStay B
影响因子：
9.2
作者：
Andersen, JS;Lyon, CE;Lamond, AI
通讯作者：
Lamond, AI
影响因子：
4
作者：
Chapman, J. Ross;Sossick, Alex J.;Jackson, Stephen P.
通讯作者：
Jackson, Stephen P.