Premium
FAM111 protease activity undermines cellular fitness and is amplified by gain‐of‐function mutations in human disease
Author(s) -
Hoffmann Saskia,
Pentakota Satyakrishna,
Mund Andreas,
Haahr Peter,
Coscia Fabian,
Gallo Marta,
Mann Matthias,
Taylor Nicholas MI,
Mailand Niels
Publication year - 2020
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.202050662
Subject(s) - biology , phenocopy , protease , proteases , genetics , microbiology and biotechnology , mutation , serine protease , dna repair , mutant , dna , gene , enzyme , biochemistry
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.