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FAM111 protease activity undermines cellular fitness and is amplified by gain‐of‐function mutations in human disease
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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534640/ https://www.ncbi.nlm.nih.gov/pubmed/32776417 http://dx.doi.org/10.15252/embr.202050662 |
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author | Hoffmann, Saskia Pentakota, Satyakrishna Mund, Andreas Haahr, Peter Coscia, Fabian Gallo, Marta Mann, Matthias Taylor, Nicholas MI Mailand, Niels |
author_facet | Hoffmann, Saskia Pentakota, Satyakrishna Mund, Andreas Haahr, Peter Coscia, Fabian Gallo, Marta Mann, Matthias Taylor, Nicholas MI Mailand, Niels |
author_sort | Hoffmann, Saskia |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7534640 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-75346402020-10-07 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 MI Mailand, Niels EMBO Rep Reports 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. John Wiley and Sons Inc. 2020-08-09 2020-10-05 /pmc/articles/PMC7534640/ /pubmed/32776417 http://dx.doi.org/10.15252/embr.202050662 Text en © 2020 The Author. Published under the terms of the CC BY NC ND 4.0 license This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Reports Hoffmann, Saskia Pentakota, Satyakrishna Mund, Andreas Haahr, Peter Coscia, Fabian Gallo, Marta Mann, Matthias Taylor, Nicholas MI Mailand, Niels FAM111 protease activity undermines cellular fitness and is amplified by gain‐of‐function mutations in human disease |
title | FAM111 protease activity undermines cellular fitness and is amplified by gain‐of‐function mutations in human disease |
title_full | FAM111 protease activity undermines cellular fitness and is amplified by gain‐of‐function mutations in human disease |
title_fullStr | FAM111 protease activity undermines cellular fitness and is amplified by gain‐of‐function mutations in human disease |
title_full_unstemmed | FAM111 protease activity undermines cellular fitness and is amplified by gain‐of‐function mutations in human disease |
title_short | FAM111 protease activity undermines cellular fitness and is amplified by gain‐of‐function mutations in human disease |
title_sort | fam111 protease activity undermines cellular fitness and is amplified by gain‐of‐function mutations in human disease |
topic | Reports |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534640/ https://www.ncbi.nlm.nih.gov/pubmed/32776417 http://dx.doi.org/10.15252/embr.202050662 |
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