The role of SLFN11 in DNA replication stress response and its implications for the Fanconi anemia pathway

IF 3 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair Pub Date : 2024-07-24 DOI:10.1016/j.dnarep.2024.103733

Anfeng Mu , Yusuke Okamoto , Yoko Katsuki , Minoru Takata

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引用次数: 0

Abstract

Fanconi anemia (FA) is a hereditary disorder characterized by a deficiency in the repair of DNA interstrand crosslinks and the response to replication stress. Endogenous DNA damage, most likely caused by aldehydes, severely affects hematopoietic stem cells in FA, resulting in progressive bone marrow failure and the development of leukemia. Recent studies revealed that expression levels of SLFN11 affect the replication stress response and are a strong determinant in cell killing by DNA-damaging cancer chemotherapy. Because SLFN11 is highly expressed in the hematopoietic system, we speculated that SLFN11 may have a significant role in FA pathophysiology. Indeed, we found that DNA damage sensitivity in FA cells is significantly mitigated by the loss of SLFN11 expression. Mechanistically, we demonstrated that SLFN11 destabilizes the nascent DNA strands upon replication fork stalling. In this review, we summarize our work regarding an interplay between SLFN11 and the FA pathway, and the role of SLFN11 in the response to replication stress.

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SLFN11 在 DNA 复制应激反应中的作用及其对范可尼贫血症通路的影响

范可尼贫血症（Fanconi anemia，FA）是一种遗传性疾病，其特点是缺乏DNA链间交联的修复能力和对复制应激的反应能力。内源性DNA损伤很可能是由醛类物质引起的，严重影响FA患者的造血干细胞，导致进行性骨髓衰竭和白血病的发生。最近的研究发现，SLFN11的表达水平影响复制应激反应，是DNA损伤性癌症化疗杀死细胞的重要决定因素。由于 SLFN11 在造血系统中高度表达，我们推测 SLFN11 可能在 FA 病理生理学中扮演重要角色。事实上，我们发现，SLFN11 的表达缺失会显著降低 FA 细胞对 DNA 损伤的敏感性。从机理上讲，我们证明 SLFN11 在复制叉停滞时会破坏新生 DNA 链的稳定性。在这篇综述中，我们总结了 SLFN11 与 FA 通路之间的相互作用，以及 SLFN11 在应对复制压力中的作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

DNA Repair 生物-毒理学

CiteScore

7.60

自引率

5.30%

发文量

审稿时长

59 days

期刊介绍： DNA Repair provides a forum for the comprehensive coverage of DNA repair and cellular responses to DNA damage. The journal publishes original observations on genetic, cellular, biochemical, structural and molecular aspects of DNA repair, mutagenesis, cell cycle regulation, apoptosis and other biological responses in cells exposed to genomic insult, as well as their relationship to human disease. DNA Repair publishes full-length research articles, brief reports on research, and reviews. The journal welcomes articles describing databases, methods and new technologies supporting research on DNA repair and responses to DNA damage. Letters to the Editor, hot topics and classics in DNA repair, historical reflections, book reviews and meeting reports also will be considered for publication.