Common Fragile Sites Are Characterized by Faulty Condensin Loading after Replication Stress.
Common Fragile Sites Are Characterized by Faulty Condensin Loading after Replication Stress.
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DOI：
10.1016/j.celrep.2020.108177
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发表时间：
2020-09-22
期刊：
影响因子：
8.8
通讯作者：
Gilbert N
中科院分区：
文献类型：
--
作者：
Boteva L;Nozawa RS;Naughton C;Samejima K;Earnshaw WC;Gilbert N
细胞协调间期到有丝分裂的转变，但在复制应激后以组织特异性方式在常见脆性位点（CFS）（称为CFS表达）出现复发性细胞遗传学病变，标志着癌症中的不稳定区域。尽管有这样一个明显的缺陷，没有一个模型完全提供了一个分子解释的CFS。我们发现，CFSs的特点是受损的染色质折叠，表现为破坏有丝分裂结构可见的分子荧光原位杂交（FISH）探针的存在和不存在的复制应力。染色体凝集试验表明，抗凋亡染色质病变持续在CFSs在整个细胞周期和有丝分裂。细胞遗传学和分子病变的标志是错误的凝聚素加载在CFSs，一个缺陷，凝聚素-I介导的压实，并符合有丝分裂DNA合成（MIDAS）。该模型表明，在外源性复制应激的条件下，异常凝聚素加载导致分子缺陷和CFS表达，同时为MIDAS提供环境，如果不解决，则导致染色体不稳定。细胞遗传学病变出现在常见的脆性位点（CFS）复制应激后CFS有受损的染色质折叠与分子荧光原位杂交探针可见CFS病变的标志是错误的凝聚素加载凝聚素耗尽增加CFS病变的频率常见的脆性位点是基因组区域，在外源性复制应激条件下表现出染色质折叠缺陷。使用FISH，Boteva et al.显示这些位点在未受干扰的条件下也改变了染色质结构，并显示错误的凝聚素加载，这导致染色质折叠缺陷和有丝分裂DNA合成。
Cells coordinate interphase-to-mitosis transition, but recurrent cytogenetic lesions appear at common fragile sites (CFSs), termed CFS expression, in a tissue-specific manner after replication stress, marking regions of instability in cancer. Despite such a distinct defect, no model fully provides a molecular explanation for CFSs. We show that CFSs are characterized by impaired chromatin folding, manifesting as disrupted mitotic structures visible with molecular fluorescence in situ hybridization (FISH) probes in the presence and absence of replication stress. Chromosome condensation assays reveal that compaction-resistant chromatin lesions persist at CFSs throughout the cell cycle and mitosis. Cytogenetic and molecular lesions are marked by faulty condensin loading at CFSs, a defect in condensin-I-mediated compaction, and are coincident with mitotic DNA synthesis (MIDAS). This model suggests that, in conditions of exogenous replication stress, aberrant condensin loading leads to molecular defects and CFS expression, concomitantly providing an environment for MIDAS, which, if not resolved, results in chromosome instability. Cytogenetic lesions appear at common fragile sites (CFSs) after replication stress CFSs have impaired chromatin folding visible with molecular FISH probes CFS lesions are marked by faulty condensin loading Condensin depletion increases the frequency of CFS lesions Common fragile sites are genomic regions that exhibit chromatin-folding defects in conditions of exogenous replication stress. Using FISH, Boteva et al. show those sites also have altered chromatin architecture in unperturbed conditions and show faulty condensin loading, which leads to chromatin-folding defects and mitotic DNA synthesis.
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