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组蛋白变体 macroH2A1 调控失活 X 染色体中复制起始点的同步激活。

Histone variant macroH2A1 regulates synchronous firing of replication origins in the inactive X chromosome.

机构信息

Cell Biology and Epigenetics, Department of Biology, Technical University of Darmstadt, 64287 Darmstadt, Germany.

Faculty of Biology and Center for Molecular Biosystems (BioSysM), Human Biology and BioImaging, LMU Munich, Munich 81377, Germany.

出版信息

Nucleic Acids Res. 2024 Oct 28;52(19):11659-11688. doi: 10.1093/nar/gkae734.

DOI:10.1093/nar/gkae734
PMID:39189450
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11514477/
Abstract

MacroH2A has been linked to transcriptional silencing, cell identity, and is a hallmark of the inactive X chromosome (Xi). However, it remains unclear whether macroH2A plays a role in DNA replication. Using knockdown/knockout cells for each macroH2A isoform, we show that macroH2A-containing nucleosomes slow down replication progression rate in the Xi reflecting the higher nucleosome stability. Moreover, macroH2A1, but not macroH2A2, regulates the number of nano replication foci in the Xi, and macroH2A1 downregulation increases DNA loop sizes corresponding to replicons. This relates to macroH2A1 regulating replicative helicase loading during G1 by interacting with it. We mapped this interaction to a phenylalanine in macroH2A1 that is not conserved in macroH2A2 and the C-terminus of Mcm3 helicase subunit. We propose that macroH2A1 enhances the licensing of pre-replication complexes via DNA helicase interaction and loading onto the Xi.

摘要

巨组蛋白 H2A 与转录沉默、细胞身份有关，是失活 X 染色体 (Xi) 的标志。然而，巨组蛋白 H2A 是否在 DNA 复制中发挥作用仍不清楚。使用针对每种巨组蛋白 H2A 异构体的敲低/敲除细胞，我们表明含有巨组蛋白 H2A 的核小体减缓了 Xi 中的复制进展速度，反映出更高的核小体稳定性。此外，巨组蛋白 H2A1 而非巨组蛋白 H2A2 调节 Xi 中的纳米复制焦点数量，并且巨组蛋白 H2A1 的下调增加了与复制子对应的 DNA 环大小。这与巨组蛋白 H2A1 通过与复制酶相互作用来调节 G1 期间复制酶加载有关。我们将这种相互作用映射到巨组蛋白 H2A1 中的一个苯丙氨酸上，该氨基酸在巨组蛋白 H2A2 中没有保守，并且在 Mcm3 解旋酶亚基的 C 末端。我们提出，巨组蛋白 H2A1 通过与 DNA 解旋酶相互作用并加载到 Xi 上来增强前复制复合物的许可。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3da/11514477/de800ee456d8/gkae734fig10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3da/11514477/b43b13c938f0/gkae734figgra1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3da/11514477/4775c3c0609f/gkae734fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3da/11514477/fa9eb12ac4b4/gkae734fig4.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3da/11514477/a247dfe731b2/gkae734fig6.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3da/11514477/5b4cdc6b8f13/gkae734fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3da/11514477/904f2e905009/gkae734fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3da/11514477/de800ee456d8/gkae734fig10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3da/11514477/b43b13c938f0/gkae734figgra1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3da/11514477/5a6600b4d2bb/gkae734fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3da/11514477/7e0c81381a3a/gkae734fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3da/11514477/4775c3c0609f/gkae734fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3da/11514477/fa9eb12ac4b4/gkae734fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3da/11514477/53862e9e0bd4/gkae734fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3da/11514477/a247dfe731b2/gkae734fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3da/11514477/629ab9cc8e09/gkae734fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3da/11514477/5b4cdc6b8f13/gkae734fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3da/11514477/904f2e905009/gkae734fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3da/11514477/de800ee456d8/gkae734fig10.jpg

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本文引用的文献

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Fork coupling directs DNA replication elongation and termination.叉形偶联指导DNA复制的延伸和终止。
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MacroH2A restricts inflammatory gene expression in melanoma cancer-associated fibroblasts by coordinating chromatin looping.MacroH2A 通过协调染色质环化来限制黑色素瘤相关成纤维细胞中的炎症基因表达。
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3D chromatin connectivity underlies replication origin efficiency in mouse embryonic stem cells.3D 染色质连接基础上的复制原点效率在小鼠胚胎干细胞。
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