The epigenetic regulator LSH maintains fork protection and genomic stability via MacroH2A deposition and RAD51 filament formation

Xiaoping Xu, Kai Ni, Yafeng He, Jianke Ren, Chongkui Sun, Yie Liu, Mirit I. Aladjem, Sandra Burkett, Richard Finney, Xia Ding, Shyam K. Sharan and Kathrin Muegge ()
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Xiaoping Xu: National Cancer Institute
Kai Ni: National Cancer Institute
Yafeng He: National Cancer Institute
Jianke Ren: National Cancer Institute
Chongkui Sun: NIH
Yie Liu: NIH
Mirit I. Aladjem: National Institutes of Health
Sandra Burkett: NIH
Richard Finney: National Cancer Institute
Xia Ding: National Cancer Institute
Shyam K. Sharan: National Cancer Institute
Kathrin Muegge: National Cancer Institute

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-23809-2

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