Mus81-Eme1-dependent aberrant processing of DNA replication intermediates in mitosis impairs genome integrity.
Mus81-Eme1-dependent aberrant processing of DNA replication intermediates in mitosis impairs genome integrity.
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DOI：
10.1126/sciadv.abc8257
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发表时间：
2020-12
期刊：
影响因子：
13.6
通讯作者：
Gottifredi V
中科院分区：
文献类型：
--
作者：
Calzetta NL;González Besteiro MA;Gottifredi V
分子剪刀Mus81修复或破坏染色体取决于有丝分裂中DNA前体的可用性。染色体不稳定性（CIN）是癌症发展的基础，并与耐药和预后不良有关。因此，了解CIN的机制基础是当务之急。已知结构特异性内切酶Mus81-Eme1可预防CIN。然而，有趣的是，我们发现Mus81-Eme1对后期复制中间体的异常处理是CIN的一个来源。当检查点激酶1 （Chk1）耗尽时，Mus81-Eme1切割参与有丝分裂DNA合成的复制不足的DNA，导致染色体分离缺陷。用核苷补充细胞可以完成有丝分裂DNA合成，抑制有丝分裂中mus81 - eme1依赖性DNA损伤和随后的CIN。我们发现有丝分裂中核苷酸短缺引起的CIN与细胞死亡之间没有相关性，它们分别与有丝分裂和S期的DNA损伤负荷选择性相关。我们的发现暗示了通过诱导细胞死亡来优化chk1导向疗法的可能性，同时减少化疗的常见副作用CIN。
The molecular scissors Mus81 fixes or ruins chromosomes depending on the availability of DNA precursors in mitosis. Chromosome instability (CIN) underpins cancer evolution and is associated with drug resistance and poor prognosis. Understanding the mechanistic basis of CIN is thus a priority. The structure-specific endonuclease Mus81-Eme1 is known to prevent CIN. Intriguingly, however, here we show that the aberrant processing of late replication intermediates by Mus81-Eme1 is a source of CIN. Upon depletion of checkpoint kinase 1 (Chk1), Mus81-Eme1 cleaves under-replicated DNA engaged in mitotic DNA synthesis, leading to chromosome segregation defects. Supplementing cells with nucleosides allows the completion of mitotic DNA synthesis, restraining Mus81-Eme1–dependent DNA damage in mitosis and the ensuing CIN. We found no correlation between CIN arising from nucleotide shortage in mitosis and cell death, which were selectively linked to DNA damage load in mitosis and S phase, respectively. Our findings imply the possibility of optimizing Chk1-directed therapies by inducing cell death while curtailing CIN, a common side effect of chemotherapy.
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影响因子：
64.8
作者：
Burrell RA;McClelland SE;Endesfelder D;Groth P;Weller MC;Shaikh N;Domingo E;Kanu N;Dewhurst SM;Gronroos E;Chew SK;Rowan AJ;Schenk A;Sheffer M;Howell M;Kschischo M;Behrens A;Helleday T;Bartek J;Tomlinson IP;Swanton C
通讯作者：
Swanton C
影响因子：
16
作者：
Buisson R;Boisvert JL;Benes CH;Zou L
通讯作者：
Zou L
影响因子：
16
作者：
Ciccia, Alberto;Ling, Chen;West, Stephen C.
通讯作者：
West, Stephen C.
影响因子：
16
作者：
Chappidi, Nagaraja;Nascakova, Zuzana;Janscak, Pavel
通讯作者：
Janscak, Pavel
DOI：
10.1083/jcb.201011083
发表时间：
2011-04-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Harrigan JA;Belotserkovskaya R;Coates J;Dimitrova DS;Polo SE;Bradshaw CR;Fraser P;Jackson SP
通讯作者：
Jackson SP