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MTBP 磷酸化控制 DNA 复制起始点的引发。

MTBP phosphorylation controls DNA replication origin firing.

机构信息

Vertebrate DNA Replication Lab, Center of Medical Biotechnology, University of Duisburg-Essen, 45117, Essen, Germany.

Max Planck Institute of Biochemistry, DNA Replication and Genome Integrity, 82152, Martinsried, Germany.

出版信息

Sci Rep. 2021 Feb 19;11(1):4242. doi: 10.1038/s41598-021-83287-w.

DOI:10.1038/s41598-021-83287-w
PMID:33608586
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7895959/
Abstract

Faithful genome duplication requires regulation of origin firing to determine loci, timing and efficiency of replisome generation. Established kinase targets for eukaryotic origin firing regulation are the Mcm2-7 helicase, Sld3/Treslin/TICRR and Sld2/RecQL4. We report that metazoan Sld7, MTBP (Mdm2 binding protein), is targeted by at least three kinase pathways. MTBP was phosphorylated at CDK consensus sites by cell cycle cyclin-dependent kinases (CDK) and Cdk8/19-cyclin C. Phospho-mimetic MTBP CDK site mutants, but not non-phosphorylatable mutants, promoted origin firing in human cells. MTBP was also phosphorylated at DNA damage checkpoint kinase consensus sites. Phospho-mimetic mutations at these sites inhibited MTBP's origin firing capability. Whilst expressing a non-phospho MTBP mutant was insufficient to relieve the suppression of origin firing upon DNA damage, the mutant induced a genome-wide increase of origin firing in unperturbed cells. Our work establishes MTBP as a regulation platform of metazoan origin firing.

摘要

忠实的基因组复制需要调节原点引发，以确定复制叉生成的位置、时间和效率。已确定的真核生物原点引发调控的激酶靶标是 Mcm2-7 解旋酶、Sld3/Treslin/TICRR 和 Sld2/RecQL4。我们报告说，后生动物 Sld7、MTBP（Mdm2 结合蛋白）是至少三种激酶途径的靶标。MTBP 被细胞周期周期蛋白依赖性激酶 (CDK) 和 Cdk8/19-cyclin C 在 CDK 保守位点磷酸化。磷酸模拟 MTBP CDK 位点突变体，但不是非磷酸化突变体，促进了人类细胞中的原点引发。MTBP 还在 DNA 损伤检查点激酶保守位点磷酸化。这些位点的磷酸模拟突变抑制了 MTBP 的原点引发能力。虽然表达非磷酸化 MTBP 突变体不足以缓解 DNA 损伤时原点引发的抑制，但该突变体在未受干扰的细胞中诱导了全基因组原点引发的增加。我们的工作确立了 MTBP 作为后生动物原点引发的调控平台。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9456/7895959/b53aa7555b7c/41598_2021_83287_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9456/7895959/0eac07ac21fb/41598_2021_83287_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9456/7895959/82d995c8c5f4/41598_2021_83287_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9456/7895959/27edb1b34b63/41598_2021_83287_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9456/7895959/3fa55ed9d4e9/41598_2021_83287_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9456/7895959/2eb36d13581d/41598_2021_83287_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9456/7895959/b53aa7555b7c/41598_2021_83287_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9456/7895959/0eac07ac21fb/41598_2021_83287_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9456/7895959/82d995c8c5f4/41598_2021_83287_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9456/7895959/27edb1b34b63/41598_2021_83287_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9456/7895959/3fa55ed9d4e9/41598_2021_83287_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9456/7895959/2eb36d13581d/41598_2021_83287_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9456/7895959/b53aa7555b7c/41598_2021_83287_Fig6_HTML.jpg

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