FAM111 protease activity undermines cellular fitness and is amplified by gain-of-function mutations in human disease
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FAM111 protease activity undermines cellular fitness and is amplified by gain-of-function mutations in human disease. / Hoffmann, Saskia; Pentakota, Satyakrishna; Mund, Andreas; Haahr, Peter; Coscia, Fabian; Gallo, Marta; Mann, Matthias; Taylor, Nicholas M.I.; Mailand, Niels.
I: EMBO Reports, Bind 21, Nr. 10, e50662, 2020.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - FAM111 protease activity undermines cellular fitness and is amplified by gain-of-function mutations in human disease
AU - Hoffmann, Saskia
AU - Pentakota, Satyakrishna
AU - Mund, Andreas
AU - Haahr, Peter
AU - Coscia, Fabian
AU - Gallo, Marta
AU - Mann, Matthias
AU - Taylor, Nicholas M.I.
AU - Mailand, Niels
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - cell fitness
KW - chromatin
KW - DNA replication
KW - human genetic disorders
KW - protease
U2 - 10.15252/embr.202050662
DO - 10.15252/embr.202050662
M3 - Journal article
C2 - 32776417
AN - SCOPUS:85089137635
VL - 21
JO - E M B O Reports
JF - E M B O Reports
SN - 1469-221X
IS - 10
M1 - e50662
ER -
ID: 247500358