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.

In: EMBO Reports, Vol. 21, No. 10, e50662, 2020.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Hoffmann, S, Pentakota, S, Mund, A, Haahr, P, Coscia, F, Gallo, M, Mann, M, Taylor, NMI & Mailand, N 2020, 'FAM111 protease activity undermines cellular fitness and is amplified by gain-of-function mutations in human disease', EMBO Reports, vol. 21, no. 10, e50662. https://doi.org/10.15252/embr.202050662

APA

Hoffmann, S., Pentakota, S., Mund, A., Haahr, P., Coscia, F., Gallo, M., Mann, M., Taylor, N. M. I., & Mailand, N. (2020). FAM111 protease activity undermines cellular fitness and is amplified by gain-of-function mutations in human disease. EMBO Reports, 21(10), [e50662]. https://doi.org/10.15252/embr.202050662

Vancouver

Hoffmann S, Pentakota S, Mund A, Haahr P, Coscia F, Gallo M et al. FAM111 protease activity undermines cellular fitness and is amplified by gain-of-function mutations in human disease. EMBO Reports. 2020;21(10). e50662. https://doi.org/10.15252/embr.202050662

Author

Hoffmann, Saskia ; Pentakota, Satyakrishna ; Mund, Andreas ; Haahr, Peter ; Coscia, Fabian ; Gallo, Marta ; Mann, Matthias ; Taylor, Nicholas M.I. ; Mailand, Niels. / FAM111 protease activity undermines cellular fitness and is amplified by gain-of-function mutations in human disease. In: EMBO Reports. 2020 ; Vol. 21, No. 10.

Bibtex

@article{8bdffc51e2504534ad3ac13cd6d78f79,
title = "FAM111 protease activity undermines cellular fitness and is amplified by gain-of-function mutations in human disease",
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",
author = "Saskia Hoffmann and Satyakrishna Pentakota and Andreas Mund and Peter Haahr and Fabian Coscia and Marta Gallo and Matthias Mann and Taylor, {Nicholas M.I.} and Niels Mailand",
year = "2020",
doi = "10.15252/embr.202050662",
language = "English",
volume = "21",
journal = "E M B O Reports",
issn = "1469-221X",
publisher = "Wiley-Blackwell",
number = "10",

}

RIS

TY - JOUR

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