Chromatin determinants of the inner-centromere rely on replication factors with functions that impart cohesion.
Chromatin determinants of the inner-centromere rely on replication factors with functions that impart cohesion.
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DOI：
10.18632/oncotarget.11982
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发表时间：
2016-10-18
期刊：
影响因子：
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通讯作者：
Branzei D
中科院分区：
文献类型：
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作者：
Abe T;Kawasumi R;Arakawa H;Hori T;Shirahige K;Losada A;Fukagawa T;Branzei D
复制分叉相关因子促进基因组完整性并预防癌症。DDX11解旋酶和ESCO2乙酰转移酶的突变也会导致相关的发育障碍，被归类为粘连疾病。在这里，我们建立了这些疾病和粘附素疾病相关基因的脊椎动物模型细胞系。我们发现脊椎动物DDX11和TIM-TIPIN分别需要补偿ESCO2在染色体分离中的丢失，DDX11在着丝粒凝聚力方面也与ESCO2起互补作用。我们的研究表明，显性着丝粒凝聚力丧失并不一定先于染色体错误分离，而这两个问题都与内着丝粒缺陷有关，并可能源于该区域组蛋白H3T3(PH3T3)的磷酸化降低。有趣的是，在所有分析的具有凝聚力功能的复制相关突变体中，有丝分裂的PH3T3标记都是缺陷的。结果表明，有丝分裂的PH3T3是一个复制后染色质标记，它对复制胁迫敏感，并以不同的动力学方式引导着丝粒凝聚力和正确的染色体分离。
Replication fork-associated factors promote genome integrity and protect against cancer. Mutations in the DDX11 helicase and the ESCO2 acetyltransferase also cause related developmental disorders classified as cohesinopathies. Here we generated vertebrate model cell lines of these disorders and cohesinopathies-related genes. We found that vertebrate DDX11 and Tim-Tipin are individually needed to compensate for ESCO2 loss in chromosome segregation, with DDX11 also playing complementary roles with ESCO2 in centromeric cohesion. Our study reveals that overt centromeric cohesion loss does not necessarily precede chromosome missegregation, while both these problems correlate with, and possibly originate from, inner-centromere defects involving reduced phosphorylation of histone H3T3 (pH3T3) in the region. Interestingly, the mitotic pH3T3 mark was defective in all analyzed replication-related mutants with functions in cohesion. The results pinpoint mitotic pH3T3 as a postreplicative chromatin mark that is sensitive to replication stress and conducts with different kinetics to robust centromeric cohesion and correct chromosome segregation.