Genome-wide CRISPR screens identify novel regulators of wild-type and mutant p53 stability

Autores
Lü, YiQing; Cho, Tiffany; Mukherjee, Saptaparna; Suarez, Carmen Florencia; González Foutel, Nicolás Sebastián; Malik, Ahmad; Martinez, Sebastien; Dervovic, Dzana; Oh, Robin Hyunseo; Langille, Ellen; Al Zahrani, Khalid N; Hoeg, Lisa; Lin, Zhen Yuan; Tsai, Ricky; Mbamalu, Geraldine; Rotter, Varda; Ashton Prolla, Patricia; Moffat, Jason; Chemes, Lucia Beatriz; Gingras, Anne Claude; Oren, Moshe; Durocher, Daniel; Schramek, Daniel
Año de publicación
2024
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Tumor suppressor p53 (TP53) is frequently mutated in cancer, often resulting not only in loss of its tumor-suppressive function but also acquisition of dominant-negative and even oncogenic gain-of-function traits. While wild-type p53 levels are tightly regulated, mutants are typically stabilized in tumors, which is crucial for their oncogenic properties. Here, we systematically profiled the factors that regulate protein stability of wild-type and mutant p53 using marker-based genome-wide CRISPR screens. Most regulators of wild-type p53 also regulate p53 mutants, except for p53 R337H regulators, which are largely private to this mutant. Mechanistically, FBXO42 emerged as a positive regulator for a subset of p53 mutants, working with CCDC6 to control USP28-mediated mutant p53 stabilization. Additionally, C16orf72/HAPSTR1 negatively regulates both wild-type p53 and all tested mutants. C16orf72/HAPSTR1 is commonly amplified in breast cancer, and its overexpression reduces p53 levels in mouse mammary epithelium leading to accelerated breast cancer. This study offers a network perspective on p53 stability regulation, potentially guiding strategies to reinforce wild-type p53 or target mutant p53 in cancer.
Fil: Lü, YiQing. University of Toronto; Canadá. Mount Sinai Hospital Toronto Ontario; Canadá
Fil: Cho, Tiffany. University of Toronto; Canadá. Mount Sinai Hospital Toronto Ontario; Canadá
Fil: Mukherjee, Saptaparna. Weizmann Institute Of Science.; Israel
Fil: Suarez, Carmen Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; Argentina
Fil: González Foutel, Nicolás Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; Argentina
Fil: Malik, Ahmad. University of Toronto; Canadá
Fil: Martinez, Sebastien. University of Toronto; Canadá
Fil: Dervovic, Dzana. University of Toronto; Canadá
Fil: Oh, Robin Hyunseo. University of Toronto; Canadá
Fil: Langille, Ellen. University of Toronto; Canadá
Fil: Al Zahrani, Khalid N. University of Toronto; Canadá
Fil: Hoeg, Lisa. University of Toronto; Canadá
Fil: Lin, Zhen Yuan. University of Toronto; Canadá
Fil: Tsai, Ricky. University of Toronto; Canadá
Fil: Mbamalu, Geraldine. University of Toronto; Canadá
Fil: Rotter, Varda. Weizmann Institute Of Science.; Israel
Fil: Ashton Prolla, Patricia. Universidade Federal do Estado do Rio de Janeiro; Brasil
Fil: Moffat, Jason. University of Toronto; Canadá
Fil: Chemes, Lucia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; Argentina
Fil: Gingras, Anne Claude. University of Toronto; Canadá
Fil: Oren, Moshe. Weizmann Institute Of Science.; Israel
Fil: Durocher, Daniel. University of Toronto; Canadá
Fil: Schramek, Daniel. University of Toronto; Canadá
Materia
BREAST CANCER
CRISPR SCREEN
p53 STABILITY
MUTANT p53
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/267392
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/267392
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Genome-wide CRISPR screens identify novel regulators of wild-type and mutant p53 stabilityLü, YiQingCho, TiffanyMukherjee, SaptaparnaSuarez, Carmen FlorenciaGonzález Foutel, Nicolás SebastiánMalik, AhmadMartinez, SebastienDervovic, DzanaOh, Robin HyunseoLangille, EllenAl Zahrani, Khalid NHoeg, LisaLin, Zhen YuanTsai, RickyMbamalu, GeraldineRotter, VardaAshton Prolla, PatriciaMoffat, JasonChemes, Lucia BeatrizGingras, Anne ClaudeOren, MosheDurocher, DanielSchramek, DanielBREAST CANCERCRISPR SCREENp53 STABILITYMUTANT p53https://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Tumor suppressor p53 (TP53) is frequently mutated in cancer, often resulting not only in loss of its tumor-suppressive function but also acquisition of dominant-negative and even oncogenic gain-of-function traits. While wild-type p53 levels are tightly regulated, mutants are typically stabilized in tumors, which is crucial for their oncogenic properties. Here, we systematically profiled the factors that regulate protein stability of wild-type and mutant p53 using marker-based genome-wide CRISPR screens. Most regulators of wild-type p53 also regulate p53 mutants, except for p53 R337H regulators, which are largely private to this mutant. Mechanistically, FBXO42 emerged as a positive regulator for a subset of p53 mutants, working with CCDC6 to control USP28-mediated mutant p53 stabilization. Additionally, C16orf72/HAPSTR1 negatively regulates both wild-type p53 and all tested mutants. C16orf72/HAPSTR1 is commonly amplified in breast cancer, and its overexpression reduces p53 levels in mouse mammary epithelium leading to accelerated breast cancer. This study offers a network perspective on p53 stability regulation, potentially guiding strategies to reinforce wild-type p53 or target mutant p53 in cancer.Fil: Lü, YiQing. University of Toronto; Canadá. Mount Sinai Hospital Toronto Ontario; CanadáFil: Cho, Tiffany. University of Toronto; Canadá. Mount Sinai Hospital Toronto Ontario; CanadáFil: Mukherjee, Saptaparna. Weizmann Institute Of Science.; IsraelFil: Suarez, Carmen Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; ArgentinaFil: González Foutel, Nicolás Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; ArgentinaFil: Malik, Ahmad. University of Toronto; CanadáFil: Martinez, Sebastien. University of Toronto; CanadáFil: Dervovic, Dzana. University of Toronto; CanadáFil: Oh, Robin Hyunseo. University of Toronto; CanadáFil: Langille, Ellen. University of Toronto; CanadáFil: Al Zahrani, Khalid N. University of Toronto; CanadáFil: Hoeg, Lisa. University of Toronto; CanadáFil: Lin, Zhen Yuan. University of Toronto; CanadáFil: Tsai, Ricky. University of Toronto; CanadáFil: Mbamalu, Geraldine. University of Toronto; CanadáFil: Rotter, Varda. Weizmann Institute Of Science.; IsraelFil: Ashton Prolla, Patricia. Universidade Federal do Estado do Rio de Janeiro; BrasilFil: Moffat, Jason. University of Toronto; CanadáFil: Chemes, Lucia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; ArgentinaFil: Gingras, Anne Claude. University of Toronto; CanadáFil: Oren, Moshe. Weizmann Institute Of Science.; IsraelFil: Durocher, Daniel. University of Toronto; CanadáFil: Schramek, Daniel. University of Toronto; CanadáNature Publishing Group2024-04info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/267392Lü, YiQing; Cho, Tiffany; Mukherjee, Saptaparna; Suarez, Carmen Florencia; González Foutel, Nicolás Sebastián; et al.; Genome-wide CRISPR screens identify novel regulators of wild-type and mutant p53 stability; Nature Publishing Group; Molecular Systems Biology; 20; 6; 4-2024; 719-7401744-4292CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.embopress.org/doi/full/10.1038/s44320-024-00032-xinfo:eu-repo/semantics/altIdentifier/doi/10.1038/s44320-024-00032-xinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:49:22Zoai:ri.conicet.gov.ar:11336/267392instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:49:22.402CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Genome-wide CRISPR screens identify novel regulators of wild-type and mutant p53 stability
title Genome-wide CRISPR screens identify novel regulators of wild-type and mutant p53 stability
spellingShingle Genome-wide CRISPR screens identify novel regulators of wild-type and mutant p53 stability
Lü, YiQing
BREAST CANCER
CRISPR SCREEN
p53 STABILITY
MUTANT p53
title_short Genome-wide CRISPR screens identify novel regulators of wild-type and mutant p53 stability
title_full Genome-wide CRISPR screens identify novel regulators of wild-type and mutant p53 stability
title_fullStr Genome-wide CRISPR screens identify novel regulators of wild-type and mutant p53 stability
title_full_unstemmed Genome-wide CRISPR screens identify novel regulators of wild-type and mutant p53 stability
title_sort Genome-wide CRISPR screens identify novel regulators of wild-type and mutant p53 stability
dc.creator.none.fl_str_mv Lü, YiQing
Cho, Tiffany
Mukherjee, Saptaparna
Suarez, Carmen Florencia
González Foutel, Nicolás Sebastián
Malik, Ahmad
Martinez, Sebastien
Dervovic, Dzana
Oh, Robin Hyunseo
Langille, Ellen
Al Zahrani, Khalid N
Hoeg, Lisa
Lin, Zhen Yuan
Tsai, Ricky
Mbamalu, Geraldine
Rotter, Varda
Ashton Prolla, Patricia
Moffat, Jason
Chemes, Lucia Beatriz
Gingras, Anne Claude
Oren, Moshe
Durocher, Daniel
Schramek, Daniel
author Lü, YiQing
author_facet Lü, YiQing
Cho, Tiffany
Mukherjee, Saptaparna
Suarez, Carmen Florencia
González Foutel, Nicolás Sebastián
Malik, Ahmad
Martinez, Sebastien
Dervovic, Dzana
Oh, Robin Hyunseo
Langille, Ellen
Al Zahrani, Khalid N
Hoeg, Lisa
Lin, Zhen Yuan
Tsai, Ricky
Mbamalu, Geraldine
Rotter, Varda
Ashton Prolla, Patricia
Moffat, Jason
Chemes, Lucia Beatriz
Gingras, Anne Claude
Oren, Moshe
Durocher, Daniel
Schramek, Daniel
author_role author
author2 Cho, Tiffany
Mukherjee, Saptaparna
Suarez, Carmen Florencia
González Foutel, Nicolás Sebastián
Malik, Ahmad
Martinez, Sebastien
Dervovic, Dzana
Oh, Robin Hyunseo
Langille, Ellen
Al Zahrani, Khalid N
Hoeg, Lisa
Lin, Zhen Yuan
Tsai, Ricky
Mbamalu, Geraldine
Rotter, Varda
Ashton Prolla, Patricia
Moffat, Jason
Chemes, Lucia Beatriz
Gingras, Anne Claude
Oren, Moshe
Durocher, Daniel
Schramek, Daniel
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv BREAST CANCER
CRISPR SCREEN
p53 STABILITY
MUTANT p53
topic BREAST CANCER
CRISPR SCREEN
p53 STABILITY
MUTANT p53
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Tumor suppressor p53 (TP53) is frequently mutated in cancer, often resulting not only in loss of its tumor-suppressive function but also acquisition of dominant-negative and even oncogenic gain-of-function traits. While wild-type p53 levels are tightly regulated, mutants are typically stabilized in tumors, which is crucial for their oncogenic properties. Here, we systematically profiled the factors that regulate protein stability of wild-type and mutant p53 using marker-based genome-wide CRISPR screens. Most regulators of wild-type p53 also regulate p53 mutants, except for p53 R337H regulators, which are largely private to this mutant. Mechanistically, FBXO42 emerged as a positive regulator for a subset of p53 mutants, working with CCDC6 to control USP28-mediated mutant p53 stabilization. Additionally, C16orf72/HAPSTR1 negatively regulates both wild-type p53 and all tested mutants. C16orf72/HAPSTR1 is commonly amplified in breast cancer, and its overexpression reduces p53 levels in mouse mammary epithelium leading to accelerated breast cancer. This study offers a network perspective on p53 stability regulation, potentially guiding strategies to reinforce wild-type p53 or target mutant p53 in cancer.
Fil: Lü, YiQing. University of Toronto; Canadá. Mount Sinai Hospital Toronto Ontario; Canadá
Fil: Cho, Tiffany. University of Toronto; Canadá. Mount Sinai Hospital Toronto Ontario; Canadá
Fil: Mukherjee, Saptaparna. Weizmann Institute Of Science.; Israel
Fil: Suarez, Carmen Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; Argentina
Fil: González Foutel, Nicolás Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; Argentina
Fil: Malik, Ahmad. University of Toronto; Canadá
Fil: Martinez, Sebastien. University of Toronto; Canadá
Fil: Dervovic, Dzana. University of Toronto; Canadá
Fil: Oh, Robin Hyunseo. University of Toronto; Canadá
Fil: Langille, Ellen. University of Toronto; Canadá
Fil: Al Zahrani, Khalid N. University of Toronto; Canadá
Fil: Hoeg, Lisa. University of Toronto; Canadá
Fil: Lin, Zhen Yuan. University of Toronto; Canadá
Fil: Tsai, Ricky. University of Toronto; Canadá
Fil: Mbamalu, Geraldine. University of Toronto; Canadá
Fil: Rotter, Varda. Weizmann Institute Of Science.; Israel
Fil: Ashton Prolla, Patricia. Universidade Federal do Estado do Rio de Janeiro; Brasil
Fil: Moffat, Jason. University of Toronto; Canadá
Fil: Chemes, Lucia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; Argentina
Fil: Gingras, Anne Claude. University of Toronto; Canadá
Fil: Oren, Moshe. Weizmann Institute Of Science.; Israel
Fil: Durocher, Daniel. University of Toronto; Canadá
Fil: Schramek, Daniel. University of Toronto; Canadá
description Tumor suppressor p53 (TP53) is frequently mutated in cancer, often resulting not only in loss of its tumor-suppressive function but also acquisition of dominant-negative and even oncogenic gain-of-function traits. While wild-type p53 levels are tightly regulated, mutants are typically stabilized in tumors, which is crucial for their oncogenic properties. Here, we systematically profiled the factors that regulate protein stability of wild-type and mutant p53 using marker-based genome-wide CRISPR screens. Most regulators of wild-type p53 also regulate p53 mutants, except for p53 R337H regulators, which are largely private to this mutant. Mechanistically, FBXO42 emerged as a positive regulator for a subset of p53 mutants, working with CCDC6 to control USP28-mediated mutant p53 stabilization. Additionally, C16orf72/HAPSTR1 negatively regulates both wild-type p53 and all tested mutants. C16orf72/HAPSTR1 is commonly amplified in breast cancer, and its overexpression reduces p53 levels in mouse mammary epithelium leading to accelerated breast cancer. This study offers a network perspective on p53 stability regulation, potentially guiding strategies to reinforce wild-type p53 or target mutant p53 in cancer.
publishDate 2024
dc.date.none.fl_str_mv 2024-04
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/267392
Lü, YiQing; Cho, Tiffany; Mukherjee, Saptaparna; Suarez, Carmen Florencia; González Foutel, Nicolás Sebastián; et al.; Genome-wide CRISPR screens identify novel regulators of wild-type and mutant p53 stability; Nature Publishing Group; Molecular Systems Biology; 20; 6; 4-2024; 719-740
1744-4292
CONICET Digital
CONICET
url http://hdl.handle.net/11336/267392
identifier_str_mv Lü, YiQing; Cho, Tiffany; Mukherjee, Saptaparna; Suarez, Carmen Florencia; González Foutel, Nicolás Sebastián; et al.; Genome-wide CRISPR screens identify novel regulators of wild-type and mutant p53 stability; Nature Publishing Group; Molecular Systems Biology; 20; 6; 4-2024; 719-740
1744-4292
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.embopress.org/doi/full/10.1038/s44320-024-00032-x
info:eu-repo/semantics/altIdentifier/doi/10.1038/s44320-024-00032-x
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.070432

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