DNA 复制蛋白 MCM10 在维持基因组稳定性中的多方面作用及其对人类疾病的影响。

IF 7.7 2区 医学 Q1 ONCOLOGY
Cancer and Metastasis Reviews Pub Date : 2024-12-01 Epub Date: 2024-09-06 DOI:10.1007/s10555-024-10209-3
Sumayyah M Q Ahmed, Jayaprakash Sasikumar, Suparna Laha, Shankar Prasad Das
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引用次数: 0

摘要

MCM10 在基因组复制中发挥着重要作用,对 DNA 复制的启动、延伸和终止至关重要。它能协调多种蛋白质在分叉处组装,形成功能性复制体,触发原点解旋,并稳定复制泡。MCM10 的过表达与乳腺癌、宫颈癌和其他几种癌症的侵袭性增加有关。MCM10 的破坏会导致复制时间的改变,与起始位点的增减有关,并伴随基因组的不稳定性。敲除 MCM10 会影响癌细胞的增殖和迁移,表现为 DNA 损伤和复制叉停滞,而且最近已证明与 CNKD 和 RCM 等临床病症有关。MCM10 功能的丧失与端粒酶活性受损有关,从而导致异常复制叉的积累和端粒长度受损。MCM10 与组蛋白相互作用,帮助核小体组装,与 BRCA2 结合以在 DNA 损伤期间保持基因组的完整性,防止病变跳过,并抑制 PRIMPOL 介导的修复。它还与分叉逆转酶 SMARCAL1 相互作用,抑制分叉回归。此外,MCM10 还会发生几种翻译后修饰,并通过与 SIR 蛋白相互作用促进转录沉默。本综述探讨了 MCM10 在 DNA 复制启动、染色质组织、转录沉默、复制应激、分叉稳定性、端粒长度维持和 DNA 损伤反应中发挥多方面作用的相关机制。最后,我们讨论了 MCM10 在癌症早期检测中的作用、其预后意义及其在癌症治疗中的潜在用途。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Multifaceted role of the DNA replication protein MCM10 in maintaining genome stability and its implication in human diseases.

Multifaceted role of the DNA replication protein MCM10 in maintaining genome stability and its implication in human diseases.

MCM10 plays a vital role in genome duplication and is crucial for DNA replication initiation, elongation, and termination. It coordinates several proteins to assemble at the fork, form a functional replisome, trigger origin unwinding, and stabilize the replication bubble. MCM10 overexpression is associated with increased aggressiveness in breast, cervical, and several other cancers. Disruption of MCM10 leads to altered replication timing associated with initiation site gains and losses accompanied by genome instability. Knockdown of MCM10 affects the proliferation and migration of cancer cells, manifested by DNA damage and replication fork arrest, and has recently been shown to be associated with clinical conditions like CNKD and RCM. Loss of MCM10 function is associated with impaired telomerase activity, leading to the accumulation of abnormal replication forks and compromised telomere length. MCM10 interacts with histones, aids in nucleosome assembly, binds BRCA2 to maintain genome integrity during DNA damage, prevents lesion skipping, and inhibits PRIMPOL-mediated repriming. It also interacts with the fork reversal enzyme SMARCAL1 and inhibits fork regression. Additionally, MCM10 undergoes several post-translational modifications and contributes to transcriptional silencing by interacting with the SIR proteins. This review explores the mechanism associated with MCM10's multifaceted role in DNA replication initiation, chromatin organization, transcriptional silencing, replication stress, fork stability, telomere length maintenance, and DNA damage response. Finally, we discuss the role of MCM10 in the early detection of cancer, its prognostic significance, and its potential use in therapeutics for cancer treatment.

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来源期刊
CiteScore
17.00
自引率
0.00%
发文量
54
审稿时长
6-12 weeks
期刊介绍: Contemporary biomedical research is on the threshold of an era in which physiological and pathological processes can be analyzed in increasingly precise and mechanistic terms.The transformation of biology from a largely descriptive, phenomenological discipline to one in which the regulatory principles can be understood and manipulated with predictability brings a new dimension to the study of cancer and the search for effective therapeutic modalities for this disease. Cancer and Metastasis Reviews provides a forum for critical review and discussion of these challenging developments. A major function of the journal is to review some of the more important and interesting recent developments in the biology and treatment of malignant disease, as well as to highlight new and promising directions, be they technological or conceptual. Contributors are encouraged to review their personal work and be speculative.
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