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MLL-WDR5-RBBP5甲基转移酶对DNA复制和染色体多倍性的调控

Regulation of DNA replication and chromosomal polyploidy by the MLL-WDR5-RBBP5 methyltransferases.

作者信息

Lu Fei, Wu Xiaojun, Yin Feng, Chia-Fang Lee Christina, Yu Min, Mihaylov Ivailo S, Yu Jiekai, Sun Hong, Zhang Hui

机构信息

Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China Basic Science Division, Nevada Cancer Institute, Las Vegas, NV 89135, USA.

Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China.

出版信息

Biol Open. 2016 Oct 15;5(10):1449-1460. doi: 10.1242/bio.019729.

DOI:10.1242/bio.019729
PMID:27744293
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5087680/
Abstract

DNA replication licensing occurs on chromatin, but how the chromatin template is regulated for replication remains mostly unclear. Here, we have analyzed the requirement of histone methyltransferases for a specific type of replication: the DNA re-replication induced by the downregulation of either Geminin, an inhibitor of replication licensing protein CDT1, or the CRL4CDT2 ubiquitin E3 ligase. We found that siRNA-mediated reduction of essential components of the MLL-WDR5-RBBP5 methyltransferase complexes including WDR5 or RBBP5, which transfer methyl groups to histone H3 at K4 (H3K4), suppressed DNA re-replication and chromosomal polyploidy. Reduction of WDR5/RBBP5 also prevented the activation of H2AX checkpoint caused by re-replication, but not by ultraviolet or X-ray irradiation; and the components of MLL complexes co-localized with the origin recognition complex (ORC) and MCM2-7 replicative helicase complexes at replication origins to control the levels of methylated H3K4. Downregulation of WDR5 or RBBP5 reduced the methylated H3K4 and suppressed the recruitment of MCM2-7 complexes onto replication origins. Our studies indicate that the MLL complexes and H3K4 methylation are required for DNA replication but not for DNA damage repair.

摘要

DNA复制许可发生在染色质上，但染色质模板如何调控复制仍大多不清楚。在此，我们分析了组蛋白甲基转移酶对特定类型复制的需求：由复制许可蛋白CDT1的抑制剂Geminin或CRL4CDT2泛素E3连接酶下调所诱导的DNA重新复制。我们发现，小干扰RNA介导的MLL-WDR5-RBBP5甲基转移酶复合物（包括WDR5或RBBP5，其将甲基基团转移至组蛋白H3的K4位点（H3K4））的必需组分减少，可抑制DNA重新复制和染色体多倍体形成。WDR5/RBBP5的减少还可阻止由重新复制而非紫外线或X射线照射所引起的H2AX检查点的激活；并且MLL复合物的组分与复制起点处的起始识别复合物（ORC）和MCM2-7复制解旋酶复合物共定位，以控制H3K4甲基化水平。WDR5或RBBP5的下调降低了H3K4甲基化水平，并抑制了MCM2-7复合物在复制起点上的募集。我们的研究表明，MLL复合物和H3K4甲基化对于DNA复制是必需的，但对于DNA损伤修复并非必需。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0db0/5087680/d3baf6900fe6/biolopen-5-019729-g7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0db0/5087680/5c9763991eda/biolopen-5-019729-g1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0db0/5087680/0a167b2af5bb/biolopen-5-019729-g6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0db0/5087680/d3baf6900fe6/biolopen-5-019729-g7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0db0/5087680/5c9763991eda/biolopen-5-019729-g1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0db0/5087680/302a3127c552/biolopen-5-019729-g2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0db0/5087680/a155ad64b9f2/biolopen-5-019729-g3.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0db0/5087680/b01ea43305f0/biolopen-5-019729-g5.jpg
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本文引用的文献

1
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Mol Cell Biol. 2014 Jan;34(2):158-79. doi: 10.1128/MCB.00631-13. Epub 2013 Nov 4.
2
Pluripotent stem cell protein Sox2 confers sensitivity to LSD1 inhibition in cancer cells.多能干细胞蛋白Sox2赋予癌细胞对LSD1抑制的敏感性。
Cell Rep. 2013 Oct 31;5(2):445-57. doi: 10.1016/j.celrep.2013.09.018. Epub 2013 Oct 17.
3
A biologist's guide to statistical thinking and analysis.
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Am J Transl Res. 2021 Mar 15;13(3):1494-1504. eCollection 2021.
4
DDB2 regulates DNA replication through PCNA-independent degradation of CDT2.DDB2通过不依赖增殖细胞核抗原（PCNA）的方式降解CDT2来调控DNA复制。
Cell Biosci. 2021 Feb 8;11(1):34. doi: 10.1186/s13578-021-00540-5.
5
Proliferating cell nuclear antigen interacts with the CRL4 ubiquitin ligase subunit CDT2 in DNA synthesis-induced degradation of CDT1.增殖细胞核抗原与 CRL4 泛素连接酶亚基 CDT2 在 DNA 合成诱导的 CDT1 降解中相互作用。
J Biol Chem. 2018 Dec 7;293(49):18879-18889. doi: 10.1074/jbc.RA118.003049. Epub 2018 Oct 9.
6
Cross-talk between Lysine-Modifying Enzymes Controls Site-Specific DNA Amplifications.赖氨酸修饰酶之间的串扰控制着特定部位的 DNA 扩增。
Cell. 2018 Aug 9;174(4):803-817.e16. doi: 10.1016/j.cell.2018.06.018. Epub 2018 Jul 26.
7
KDM5B demethylates H3K4 to recruit XRCC1 and promote chemoresistance.KDM5B 通过去甲基化 H3K4 来招募 XRCC1 并促进化学抗性。
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8
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4
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6
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7
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8
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9
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Nat Cell Biol. 2010 Nov;12(11):1086-93. doi: 10.1038/ncb2113. Epub 2010 Oct 17.
10
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Cell. 2010 Sep 17;142(6):967-80. doi: 10.1016/j.cell.2010.08.020.