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复制体相关组蛋白 H3-H4 伴侣蛋白，对于表观遗传遗传是必需的。

A replisome-associated histone H3-H4 chaperone required for epigenetic inheritance.

机构信息

Howard Hughes Medical Institute, Department of Cell Biology, Harvard Medical School, Boston, MA, USA.

State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.

出版信息

Cell. 2024 Sep 5;187(18):5010-5028.e24. doi: 10.1016/j.cell.2024.07.006. Epub 2024 Aug 1.

DOI:10.1016/j.cell.2024.07.006
PMID:39094570
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11380579/
Abstract

Faithful transfer of parental histones to newly replicated daughter DNA strands is critical for inheritance of epigenetic states. Although replication proteins that facilitate parental histone transfer have been identified, how intact histone H3-H4 tetramers travel from the front to the back of the replication fork remains unknown. Here, we use AlphaFold-Multimer structural predictions combined with biochemical and genetic approaches to identify the Mrc1/CLASPIN subunit of the replisome as a histone chaperone. Mrc1 contains a conserved histone-binding domain that forms a brace around the H3-H4 tetramer mimicking nucleosomal DNA and H2A-H2B histones, is required for heterochromatin inheritance, and promotes parental histone recycling during replication. We further identify binding sites for the FACT histone chaperone in Swi1/TIMELESS and DNA polymerase α that are required for heterochromatin inheritance. We propose that Mrc1, in concert with FACT acting as a mobile co-chaperone, coordinates the distribution of parental histones to newly replicated DNA.

摘要

亲代组蛋白忠实传递到新复制的女儿 DNA 链对于表观遗传状态的遗传至关重要。虽然已经鉴定出促进亲本组蛋白转移的复制蛋白，但完整的组蛋白 H3-H4 四聚体如何从前到后穿过复制叉仍然未知。在这里，我们使用 AlphaFold-Multimer 结构预测结合生化和遗传方法，将复制体的 Mrc1/CLASPIN 亚基鉴定为组蛋白伴侣。Mrc1 包含一个保守的组蛋白结合结构域，该结构域围绕 H3-H4 四聚体形成一个支架，模拟核小体 DNA 和 H2A-H2B 组蛋白，是异染色质遗传所必需的，并促进复制过程中亲本组蛋白的回收。我们进一步确定了 Swi1/TIMELESS 和 DNA 聚合酶α中 FACT 组蛋白伴侣的结合位点，这些位点对于异染色质遗传是必需的。我们提出，Mrc1 与作为移动共伴侣的 FACT 协同作用，协调亲本组蛋白在新复制 DNA 上的分布。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0df0/11380579/f0fbc4cb5172/nihms-2018534-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0df0/11380579/0c54b937c351/nihms-2018534-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0df0/11380579/8e3d5906020d/nihms-2018534-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0df0/11380579/6ae17b5745e6/nihms-2018534-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0df0/11380579/0323b0b8b272/nihms-2018534-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0df0/11380579/42dbe626079f/nihms-2018534-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0df0/11380579/d391cf2d24f2/nihms-2018534-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0df0/11380579/f0fbc4cb5172/nihms-2018534-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0df0/11380579/0c54b937c351/nihms-2018534-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0df0/11380579/8e3d5906020d/nihms-2018534-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0df0/11380579/6ae17b5745e6/nihms-2018534-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0df0/11380579/0323b0b8b272/nihms-2018534-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0df0/11380579/42dbe626079f/nihms-2018534-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0df0/11380579/d391cf2d24f2/nihms-2018534-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0df0/11380579/f0fbc4cb5172/nihms-2018534-f0008.jpg

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