期刊
NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -出版社
NATURE RESEARCH
DOI: 10.1038/s41467-021-21878-x
关键词
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资金
- NIH [GM074917, GM134681, GM083024, GM102413, CA190492, GM118047, T32-CA009138]
- NSF [DGE-1144081]
- UNC Dissertation Completion Fellowship
- NIH National Center for Advancing Translational Sciences [TL1R002493, UL1TR002494]
- ARCS Foundation
- National Institute for Health Research Oxford Biomedical Research Centre Program
- Health Innovation Challenge Fund [R6-388/WT 100127]
- Wellcome Trust
- Department of Health
- [P30 CA077598]
- [P30 CA016086]
MCM10 deficiency results in chronic replication stress, reducing cell viability due to increased genomic instability and telomere erosion. Loss of MCM10 function constrains telomerase activity, potentially leading to a build-up of abnormal replication structures and terminally-arrested replication forks that require processing by MUS81.
Minichromosome maintenance protein 10 (MCM10) is essential for eukaryotic DNA replication. Here, we describe compound heterozygous MCM10 variants in patients with distinctive, but overlapping, clinical phenotypes: natural killer (NK) cell deficiency (NKD) and restrictive cardiomyopathy (RCM) with hypoplasia of the spleen and thymus. To understand the mechanism of MCM10-associated disease, we modeled these variants in human cell lines. MCM10 deficiency causes chronic replication stress that reduces cell viability due to increased genomic instability and telomere erosion. Our data suggest that loss of MCM10 function constrains telomerase activity by accumulating abnormal replication fork structures enriched with single-stranded DNA. Terminally-arrested replication forks in MCM10-deficient cells require endonucleolytic processing by MUS81, as MCM10:MUS81 double mutants display decreased viability and accelerated telomere shortening. We propose that these bi-allelic variants in MCM10 predispose specific cardiac and immune cell lineages to prematurely arrest during differentiation, causing the clinical phenotypes observed in both NKD and RCM patients. Minichromosome maintenance protein 10 (MCM10) is critical for eukaryotic DNA replication. Here, by modelling MCM10 variants in human cell lines, the authors reveal a mechanism of MCM10-associated disease, finding that loss of MCM10 function constrains telomerase activity.
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