期刊
EMBO REPORTS
卷 21, 期 10, 页码 -出版社
WILEY
DOI: 10.15252/embr.202050662
关键词
cell fitness; chromatin; DNA replication; human genetic disorders; protease
资金
- Novo Nordisk Foundation [NNF14CC0001, NNF18OC0030752]
- Lundbeck Foundation [R303-2018-3212]
- European Research Council (ERC) [616236]
- Danish Cancer Society [R231-A13972]
- Danish National Research Foundation [DNRF115]
- European Research Council (ERC) [616236] Funding Source: European Research Council (ERC)
Dominant missense mutations in the human serine protease FAM111A underlie perinatally lethal gracile bone dysplasia and Kenny-Caffey syndrome, yet howFAM111Amutations lead to disease is not known. We show that FAM111A proteolytic activity suppresses DNA replication and transcription by displacing key effectors of these processes from chromatin, triggering rapid programmed cell death by Caspase-dependent apoptosis to potently undermine cell viability. Patient-associated point mutations in FAM111A exacerbate these phenotypes by hyperactivating its intrinsic protease activity. Moreover, FAM111A forms a complex with the uncharacterized homologous serine protease FAM111B, point mutations in which cause a hereditary fibrosing poikiloderma syndrome, and we demonstrate that disease-associated FAM111B mutants display amplified proteolytic activity and phenocopy the cellular impact of deregulated FAM111A catalytic activity. Thus, patient-associatedFAM111AandFAM111Bmutations may drive multisystem disorders via a common gain-of-function mechanism that relieves inhibitory constraints on their protease activities to powerfully undermine cellular fitness.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据