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细胞周期蛋白依赖性激酶（CDK）介导的磷酸化作用在DNA复制过程中调节多聚核苷酸激酶3'-磷酸酶（PNKP）的功能。

CDK-dependent phosphorylation regulates PNKP function in DNA replication.

作者信息

Mashayekhi Fatemeh, Zeinali Elham, Ganje Cassandra, Fanta Mesfin, Li Lei, Godbout Roseline, Weinfeld Michael, Ismail Ismail Hassan

机构信息

Department of Oncology, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada.

Department of Oncology, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada.

出版信息

J Biol Chem. 2024 Nov;300(11):107880. doi: 10.1016/j.jbc.2024.107880. Epub 2024 Oct 11.

DOI:10.1016/j.jbc.2024.107880
PMID:39395804
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11650725/
Abstract

Okazaki fragment maturation (OFM) stands as a pivotal DNA metabolic process, crucial for genome integrity and cell viability. Dysregulation of OFM leads to DNA single-strand breaks-accumulation, which is linked to various human diseases such as cancer and neurodegenerative disorders. Recent studies have implicated LIG3-XRCC1 acting in an alternative OFM pathway to the canonical FEN1-LIG1 pathway. Here, we reveal that polynucleotide kinase-phosphatase (PNKP) is another key participant in DNA replication, akin to LIG3-XRCC1. Through functional experiments, we demonstrate PNKP's enrichment at DNA replication forks and its association with PCNA, indicating its involvement in DNA replication processes. Cellular depletion of PNKP mirrors defects observed in OFM-related proteins, highlighting its significance in replication fork dynamics. Additionally, we identify PNKP as a substrate for cyclin-dependent kinase 1 and 2 (CDK1/2), which phosphorylates PNKP at multiple residues. Mutation analysis of these phosphorylation sites underscores the importance of CDK-mediated PNKP phosphorylation in DNA replication. Our findings collectively indicate a novel role for PNKP in facilitating Okazaki fragments joining, thus shedding light on its contribution to genome stability maintenance.

摘要

冈崎片段成熟（OFM）是一个关键的DNA代谢过程，对基因组完整性和细胞活力至关重要。OFM失调会导致DNA单链断裂积累，这与各种人类疾病如癌症和神经退行性疾病有关。最近的研究表明，LIG3-XRCC1在一条替代于经典FEN1-LIG1途径的OFM途径中发挥作用。在这里，我们揭示多核苷酸激酶-磷酸酶（PNKP）是DNA复制中的另一个关键参与者，与LIG3-XRCC1类似。通过功能实验，我们证明PNKP在DNA复制叉处富集并与增殖细胞核抗原（PCNA）相关联，表明其参与DNA复制过程。细胞中PNKP的缺失反映了在OFM相关蛋白中观察到的缺陷，突出了其在复制叉动态中的重要性。此外，我们确定PNKP是细胞周期蛋白依赖性激酶1和2（CDK1/2）的底物，CDK1/2在多个残基处使PNKP磷酸化。这些磷酸化位点的突变分析强调了CDK介导的PNKP磷酸化在DNA复制中的重要性。我们的研究结果共同表明PNKP在促进冈崎片段连接中具有新作用，从而揭示了其对维持基因组稳定性的贡献。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b306/11650725/93b6ab864310/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b306/11650725/284eb527d763/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b306/11650725/eec8e9be604c/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b306/11650725/80588920926a/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b306/11650725/78ffadb92761/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b306/11650725/37a3bcd61fc8/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b306/11650725/9c5ccf5150ca/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b306/11650725/93b6ab864310/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b306/11650725/284eb527d763/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b306/11650725/eec8e9be604c/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b306/11650725/80588920926a/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b306/11650725/78ffadb92761/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b306/11650725/37a3bcd61fc8/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b306/11650725/9c5ccf5150ca/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b306/11650725/93b6ab864310/gr7.jpg

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