STK39介导的γ-H2A.X扩增可促进同源重组并导致PARP抑制剂抗性。

IF 16.6 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Yi Xu, Changying Li, Huan Yin, Somaira Nowsheen, Xin Xu, Wenjuan Kang, Xin Liu, Lifeng Chen, Zhenkun Lou, Junlin Yi, Min Deng
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引用次数: 0

摘要

组蛋白 H2A.X 磷酸化成 γH2A.X 是 DNA 损伤反应中一个关键的早期事件,它标记 DNA 损伤位点并启动修复过程。传统上,ATM 激酶被认为是 H2A.X 磷酸化的主要介质,而我们的研究发现丝氨酸/苏氨酸激酶 39(STK39)是这一关键信号通路的新型增强因子。我们证明,DNA损伤后,STK39会被ATM激酶磷酸化,促进其与Mre11-Rad50-Nbs1复合物的相互作用,并随后被招募到染色质中。这种招募使 STK39 能够进一步磷酸化 H2A.X,从而扩大γH2A.X 的产生并促进同源重组修复。值得注意的是,我们在胰腺腺癌(PAAD)组织中观察到 STK39 的显著上调,这与 PARPi 治疗的耐药性增强有关。此外,我们还证明了 STK39 抑制剂与 PARP 抑制剂联合使用在抑制和逆转 PAAD 生长方面的协同疗效。这项研究不仅为 H2A.X 磷酸化的分子动力学提供了新的见解,而且突出了靶向 STK39 提高 PAAD 对 PARPi 敏感性的治疗潜力(使用 BioRender 创建)。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
STK39-mediated amplification of γ-H2A.X promotes homologous recombination and contributes to PARP inhibitor resistance.

The phosphorylation of histone H2A.X into γH2A.X is a crucial early event in the DNA damage response, marking DNA damage sites and initiating repair processes. While ATM kinase is traditionally recognized as the primary mediator of H2A.X phosphorylation, our study identifies serine/threonine kinase 39 (STK39) as a novel enhancer of this critical signaling pathway. We demonstrate that after DNA damage, STK39 undergoes phosphorylation by the ATM kinase, facilitating its interaction with the Mre11-Rad50-Nbs1 complex and subsequent recruitment to chromatin. This recruitment enables STK39 to further phosphorylate H2A.X, thus amplifying γH2A.X production and promoting homologous recombination repair. Notably, we observe a significant upregulation of STK39 in pancreatic adenocarcinoma (PAAD) tissues, correlating with heightened resistance to PARPi therapy. Furthermore, we demonstrate the synergistic efficacy of combining STK39 inhibition with PARP inhibitors in suppressing and reversing PAAD growth. This study not only provides new insights into the molecular dynamics of H2A.X phosphorylation but also highlights the therapeutic potential of targeting STK39 to enhance PARPi sensitivity in PAAD (created with BioRender).

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来源期刊
Nucleic Acids Research
Nucleic Acids Research 生物-生化与分子生物学
CiteScore
27.10
自引率
4.70%
发文量
1057
审稿时长
2 months
期刊介绍: Nucleic Acids Research (NAR) is a scientific journal that publishes research on various aspects of nucleic acids and proteins involved in nucleic acid metabolism and interactions. It covers areas such as chemistry and synthetic biology, computational biology, gene regulation, chromatin and epigenetics, genome integrity, repair and replication, genomics, molecular biology, nucleic acid enzymes, RNA, and structural biology. The journal also includes a Survey and Summary section for brief reviews. Additionally, each year, the first issue is dedicated to biological databases, and an issue in July focuses on web-based software resources for the biological community. Nucleic Acids Research is indexed by several services including Abstracts on Hygiene and Communicable Diseases, Animal Breeding Abstracts, Agricultural Engineering Abstracts, Agbiotech News and Information, BIOSIS Previews, CAB Abstracts, and EMBASE.
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