Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening.
Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening.
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与免疫功能障碍和心肌病相关的双等位基因MCM10变异导致端粒缩短。
DOI：
10.1038/s41467-021-21878-x
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发表时间：
2021-03-12
影响因子：
16.6
通讯作者：
Bielinsky AK
中科院分区：
文献类型：
--
作者：
Baxley RM;Leung W;Schmit MM;Matson JP;Yin L;Oram MK;Wang L;Taylor J;Hedberg J;Rogers CB;Harvey AJ;Basu D;Taylor JC;Pagnamenta AT;Dreau H;Craft J;Ormondroyd E;Watkins H;Hendrickson EA;Mace EM;Orange JS;Aihara H;Stewart GS;Blair E;Cook JG;Bielinsky AK
微小染色体维持蛋白10（MCM10）是真核生物DNA复制所必需的蛋白质。在这里，我们描述了复合杂合MCM10变异体的患者具有独特的，但重叠的临床表型：自然杀伤（NK）细胞缺乏症（NKD）和限制性心肌病（RCM）与发育不全的脾脏和胸腺。为了了解MCM10相关疾病的机制，我们在人类细胞系中模拟了这些变异。MCM10缺陷导致慢性复制应激，其由于增加的基因组不稳定性和端粒侵蚀而降低细胞活力。我们的数据表明，MCM10功能的丧失通过积累富含单链DNA的异常复制叉结构来抑制端粒酶活性。在MCM10缺陷细胞中，终末停滞的复制叉需要由MUS81进行核酸内切处理，因为MCM10：MUS81双突变体显示出活力降低和端粒缩短加速。我们认为，MCM10中的这些双等位基因变体使特定的心脏和免疫细胞谱系在分化过程中过早停滞，导致在NKD和RCM患者中观察到的临床表型。微小染色体维持蛋白10（MCM10）是真核生物DNA复制的关键蛋白。在这里，通过模拟人类细胞系中的MCM10变体，作者揭示了MCM10相关疾病的机制，发现MCM10功能的丧失抑制了端粒酶活性。
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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影响因子：
15.9
作者：
Gineau, Laure;Cognet, Celine;Jouanguy, Emmanuelle
通讯作者：
Jouanguy, Emmanuelle
影响因子：
16.6
作者：
Bianco, Julien N.;Bergoglio, Valerie;Pasero, Philippe
通讯作者：
Pasero, Philippe
DOI：
10.1073/pnas.0911500106
发表时间：
2009-12-01
影响因子：
11.1
作者：
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通讯作者：
Speck, Christian
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14.9
作者：
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通讯作者：
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作者：
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通讯作者：
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