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首页> 外文期刊>Nucleic Acids Research >Reduction of nucleosome assembly during new DNA synthesis impairs both major pathways of double-strand break repair.
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Reduction of nucleosome assembly during new DNA synthesis impairs both major pathways of double-strand break repair.

机译：在新的DNA合成过程中核小体装配的减少损害了双链断裂修复的两个主要途径。

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Assembly of new chromatin during S phase requires the histone chaperone complexes CAF-1 (Cac2p, Msi1p and Rlf2p) and RCAF (Asf1p plus acetylated histones H3 and H4). Cells lacking CAF-1 and RCAF are hypersensitive to DNA-damaging agents, such as methyl methanesulfonate and camptothecin, suggesting a possible defect in double-strand break (DSB) repair. Assays developed to quantitate repair of defined, cohesive-ended break structures revealed that DSB-induced plasmid:chromosome recombination was reduced approximately 10-fold in RCAF/CAF-1 double mutants. Recombination defects were similar with both chromosomal and plasmid targets in vivo, suggesting that inhibitory chromatin structures were not involved. Consistent with these observations, ionizing radiation-induced loss of heterozygosity was abolished in the mutants. Nonhomologous end-joining (NHEJ) repair proficiency and accuracy were intermediate between wild-type levels and those of NHEJ-deficient yku70 and rad50 mutants. The defects in NHEJ, but nothomologous recombination, could be rescued by deletion of HMR-a1, a component of the a1/alpha2 transcriptional repressor complex. The findings are consistent with the observation that silent mating loci are partially derepressed. These results demonstrate that defective assembly of nucleosomes during new DNA synthesis compromises each of the known pathways of DSB repair and that the effects can be indirect consequences of changes in silenced chromatin structure.
机译：在S期组装新的染色质需要组蛋白伴侣复合物CAF-1（Cac2p，Msi1p和Rlf2p）和RCAF（Asf1p加上乙酰化的组蛋白H3和H4）。缺乏CAF-1和RCAF的细胞对DNA破坏剂（如甲磺酸甲酯和喜树碱）过敏，这表明双链断裂（DSB）修复可能存在缺陷。建立定量修复确定的，内聚末端断裂结构的分析方法，发现在RCAF / CAF-1双重突变体中，DSB诱导的质粒：染色体重组减少了约10倍。重组缺陷与体内染色体靶和质粒靶相似，表明不涉及抑制性染色质结构。与这些观察结果一致，突变体中消除了电离辐射引起的杂合性丧失。非同源末端连接（NHEJ）修复能力和准确性介于野生型水平和NHEJ缺陷yku70和rad50突变体之间。 NHEJ中的缺陷，但不是同源重组，可以通过缺失HMR-a1（a1 / alpha2转录阻遏物复合体的一个成分）来挽救。该发现与沉默交配基因座被部分抑制的观察结果一致。这些结果表明，在新的DNA合成过程中核小体的组装缺陷会损害DSB修复的每个已知途径，并且这种影响可能是沉默染色质结构改变的间接后果。

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