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The epigenetic regulator LSH maintains fork protection and genomic stability via MacroH2A deposition and RAD51 filament formation
The Immunodeficiency Centromeric Instability Facial Anomalies (ICF) 4 syndrome is caused by mutations in LSH/HELLS, a chromatin remodeler promoting incorporation of histone variant macroH2A. Here, we demonstrate that LSH depletion results in degradation of nascent DNA at stalled replication forks an...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192551/ https://www.ncbi.nlm.nih.gov/pubmed/34112784 http://dx.doi.org/10.1038/s41467-021-23809-2 |
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author | Xu, Xiaoping Ni, Kai He, Yafeng Ren, Jianke Sun, Chongkui Liu, Yie Aladjem, Mirit I. Burkett, Sandra Finney, Richard Ding, Xia Sharan, Shyam K. Muegge, Kathrin |
author_facet | Xu, Xiaoping Ni, Kai He, Yafeng Ren, Jianke Sun, Chongkui Liu, Yie Aladjem, Mirit I. Burkett, Sandra Finney, Richard Ding, Xia Sharan, Shyam K. Muegge, Kathrin |
author_sort | Xu, Xiaoping |
collection | PubMed |
description | The Immunodeficiency Centromeric Instability Facial Anomalies (ICF) 4 syndrome is caused by mutations in LSH/HELLS, a chromatin remodeler promoting incorporation of histone variant macroH2A. Here, we demonstrate that LSH depletion results in degradation of nascent DNA at stalled replication forks and the generation of genomic instability. The protection of stalled forks is mediated by macroH2A, whose knockdown mimics LSH depletion and whose overexpression rescues nascent DNA degradation. LSH or macroH2A deficiency leads to an impairment of RAD51 loading, a factor that prevents MRE11 and EXO1 mediated nascent DNA degradation. The defect in RAD51 loading is linked to a disbalance of BRCA1 and 53BP1 accumulation at stalled forks. This is associated with perturbed histone modifications, including abnormal H4K20 methylation that is critical for BRCA1 enrichment and 53BP1 exclusion. Altogether, our results illuminate the mechanism underlying a human syndrome and reveal a critical role of LSH mediated chromatin remodeling in genomic stability. |
format | Online Article Text |
id | pubmed-8192551 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-81925512021-06-17 The epigenetic regulator LSH maintains fork protection and genomic stability via MacroH2A deposition and RAD51 filament formation Xu, Xiaoping Ni, Kai He, Yafeng Ren, Jianke Sun, Chongkui Liu, Yie Aladjem, Mirit I. Burkett, Sandra Finney, Richard Ding, Xia Sharan, Shyam K. Muegge, Kathrin Nat Commun Article The Immunodeficiency Centromeric Instability Facial Anomalies (ICF) 4 syndrome is caused by mutations in LSH/HELLS, a chromatin remodeler promoting incorporation of histone variant macroH2A. Here, we demonstrate that LSH depletion results in degradation of nascent DNA at stalled replication forks and the generation of genomic instability. The protection of stalled forks is mediated by macroH2A, whose knockdown mimics LSH depletion and whose overexpression rescues nascent DNA degradation. LSH or macroH2A deficiency leads to an impairment of RAD51 loading, a factor that prevents MRE11 and EXO1 mediated nascent DNA degradation. The defect in RAD51 loading is linked to a disbalance of BRCA1 and 53BP1 accumulation at stalled forks. This is associated with perturbed histone modifications, including abnormal H4K20 methylation that is critical for BRCA1 enrichment and 53BP1 exclusion. Altogether, our results illuminate the mechanism underlying a human syndrome and reveal a critical role of LSH mediated chromatin remodeling in genomic stability. Nature Publishing Group UK 2021-06-10 /pmc/articles/PMC8192551/ /pubmed/34112784 http://dx.doi.org/10.1038/s41467-021-23809-2 Text en © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Xu, Xiaoping Ni, Kai He, Yafeng Ren, Jianke Sun, Chongkui Liu, Yie Aladjem, Mirit I. Burkett, Sandra Finney, Richard Ding, Xia Sharan, Shyam K. Muegge, Kathrin The epigenetic regulator LSH maintains fork protection and genomic stability via MacroH2A deposition and RAD51 filament formation |
title | The epigenetic regulator LSH maintains fork protection and genomic stability via MacroH2A deposition and RAD51 filament formation |
title_full | The epigenetic regulator LSH maintains fork protection and genomic stability via MacroH2A deposition and RAD51 filament formation |
title_fullStr | The epigenetic regulator LSH maintains fork protection and genomic stability via MacroH2A deposition and RAD51 filament formation |
title_full_unstemmed | The epigenetic regulator LSH maintains fork protection and genomic stability via MacroH2A deposition and RAD51 filament formation |
title_short | The epigenetic regulator LSH maintains fork protection and genomic stability via MacroH2A deposition and RAD51 filament formation |
title_sort | epigenetic regulator lsh maintains fork protection and genomic stability via macroh2a deposition and rad51 filament formation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192551/ https://www.ncbi.nlm.nih.gov/pubmed/34112784 http://dx.doi.org/10.1038/s41467-021-23809-2 |
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