DNA聚合酶α-引物酶复合物的激酶调控：来自十年来全球磷酸化蛋白质组学的推断

IF 0.9 Q4 GENETICS & HEREDITY

Gene Reports Pub Date : 2025-08-04 DOI:10.1016/j.genrep.2025.102312

Aromal Monipillil Ajayakumar , Athira Perunelly Gopalakrishnan , Amal Fahma , Althaf Mahin , Suhail Subair , Prathik Basthikoppa Shivamurthy , Poornima Ramesh , Rajesh Raju

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引用次数: 0

摘要

DNA聚合酶α-引物酶（polα-primase）复合体是DNA复制的关键，它是催化（POLA1）、调控（POLA2）和引物酶（PRIM1和PRIM2）亚基的结合产物。POLA1扩展引物酶亚基合成的引物，而POLA2与包括and -1在内的复制因子相互作用，并参与复制机制的组装。这篇综述介绍了调节polα-引物酶复合物的激酶介导的磷酸化调控网络的特征，并特别关注在POLA1上鉴定的磷酸化位点。此外，基于质谱的磷酸化蛋白质组学数据整合，讨论了polα-引物酶亚基之间的共差异调控模式。利用当前磷酸化位点激酶定位资源，强调了可能负责磷酸化polα-引物酶复合物的候选上游激酶。这些激酶以位点特异性的方式调节polα-引物酶复合物的活性，将其功能整合到关键的细胞过程中，如DNA损伤反应、免疫信号传导和致癌转化。虽然存在大量的知识，特别是在全局磷酸化调控方面，但关键的空白仍然存在，特别是在实验验证的，位点特异性的polα-引物酶复合物磷酸化的功能研究中。这篇综述不仅强调了关键的监管机制，而且为未来的有针对性的调查铺平了道路，其中一些正在积极探索中。

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Kinase regulation of DNA polymerase alpha - primase (polα-primase) complex: Inference from decade-long global phosphoproteomes

DNA polymerase alpha - primase (polα-primase) complex is crucial for DNA replication, which is an association of catalytic (POLA1), regulatory (POLA2) and primase (PRIM1 and PRIM2) subunits. POLA1 extends the primers synthesized by the primase subunits, while POLA2 interacts with the replication factors including AND-1 and contributes to the assembly of replication machinery. This review presents a characterization of the kinase-mediated phosphoregulatory network regulating the polα-primase complex, with a specific focus on phosphorylation sites identified on POLA1. In addition, patterns of co-differential regulation among polα-primase subunits are discussed based on mass spectrometry-based phosphoproteomics data integration. The candidate upstream kinases potentially responsible for phosphorylating polα-primase complex are highlighted, drawing on current phosphorylation site–kinase mapping resources. These kinases modulate polα-primase complex activity in a site-specific manner, integrating its function into key cellular processes such as the DNA damage response, immune signaling, and oncogenic transformation. While substantial knowledge exists, particularly on global phosphoregulation, critical gaps remain especially in experimentally validated, site-specific functional studies of polα-primase complex phosphorylation. This review not only highlights key regulatory mechanisms but also paves the way for targeted investigations in the future, some of which are now actively being explored.

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来源期刊

Gene Reports Biochemistry, Genetics and Molecular Biology-Genetics

CiteScore

3.30

自引率

7.70%

发文量

246

审稿时长

49 days

期刊介绍： Gene Reports publishes papers that focus on the regulation, expression, function and evolution of genes in all biological contexts, including all prokaryotic and eukaryotic organisms, as well as viruses. Gene Reports strives to be a very diverse journal and topics in all fields will be considered for publication. Although not limited to the following, some general topics include: DNA Organization, Replication & Evolution -Focus on genomic DNA (chromosomal organization, comparative genomics, DNA replication, DNA repair, mobile DNA, mitochondrial DNA, chloroplast DNA). Expression & Function - Focus on functional RNAs (microRNAs, tRNAs, rRNAs, mRNA splicing, alternative polyadenylation) Regulation - Focus on processes that mediate gene-read out (epigenetics, chromatin, histone code, transcription, translation, protein degradation). Cell Signaling - Focus on mechanisms that control information flow into the nucleus to control gene expression (kinase and phosphatase pathways controlled by extra-cellular ligands, Wnt, Notch, TGFbeta/BMPs, FGFs, IGFs etc.) Profiling of gene expression and genetic variation - Focus on high throughput approaches (e.g., DeepSeq, ChIP-Seq, Affymetrix microarrays, proteomics) that define gene regulatory circuitry, molecular pathways and protein/protein networks. Genetics - Focus on development in model organisms (e.g., mouse, frog, fruit fly, worm), human genetic variation, population genetics, as well as agricultural and veterinary genetics. Molecular Pathology & Regenerative Medicine - Focus on the deregulation of molecular processes in human diseases and mechanisms supporting regeneration of tissues through pluripotent or multipotent stem cells.