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FAM111 protease activity undermines cellular fitness and is amplified by gain-of-function mutations in human disease

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Item Type:Article
Title:FAM111 protease activity undermines cellular fitness and is amplified by gain-of-function mutations in human disease
Creators Name:Hoffmann, S. and Pentakota, S. and Mund, A. and Haahr, P. and Coscia, F. and Gallo, M. and Mann, M. and Taylor, N.M. and Mailand, N.
Abstract:Dominant missense mutations in the human serine protease FAM111A underlie perinatally lethal gracile bone dysplasia and Kenny-Caffey syndrome, yet how FAM111A mutations 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-associated FAM111A and FAM111B mutations may drive multisystem disorders via a common gain-of-function mechanism that relieves inhibitory constraints on their protease activities to powerfully undermine cellular fitness.
Keywords:Cell Fitness, Chromatin, DNA Replication, Human Genetic Disorders, Protease
Source:EMBO Reports
ISSN:1469-221X
Publisher:Nature Publishing Group
Volume:21
Number:10
Page Range:e50662
Date:5 October 2020
Official Publication:https://doi.org/10.15252/embr.202050662
PubMed:View item in PubMed

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