SLFN11 在 DNA 复制应激反应中的作用及其对范可尼贫血途径的影响。

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

机构信息

Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto, Japan; Multilayer Network Research Unit, Research Coordination Alliance, Kyoto University, Kyoto, Japan.

Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto, Japan; Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

出版信息

DNA Repair (Amst). 2024 Sep;141:103733. doi: 10.1016/j.dnarep.2024.103733. Epub 2024 Jul 24.

DOI:10.1016/j.dnarep.2024.103733

PMID:39096698

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.

摘要

范可尼贫血症（FA）是一种遗传性疾病，其特征是 DNA 链间交联的修复缺陷以及对复制应激的反应。内源性 DNA 损伤，很可能是由醛类引起的，严重影响 FA 中的造血干细胞，导致进行性骨髓衰竭和白血病的发展。最近的研究表明，SLFN11 的表达水平影响复制应激反应，并且是 DNA 损伤癌症化疗导致细胞杀伤的一个强有力决定因素。由于 SLFN11 在造血系统中高度表达，我们推测 SLFN11 可能在 FA 病理生理学中具有重要作用。事实上，我们发现 FA 细胞中的 DNA 损伤敏感性通过 SLFN11 表达的丧失而显著减轻。从机制上讲，我们证明了 SLFN11 在复制叉停滞时使新生 DNA 链不稳定。在这篇综述中，我们总结了我们关于 SLFN11 与 FA 途径之间相互作用以及 SLFN11 在复制应激反应中的作用的工作。