MiR223-3p promotes synthetic lethality in BRCA1-deficient cancers.
3' Untranslated Regions
BRCA1 Protein
/ deficiency
Cell Line, Tumor
DNA Repair
DNA Replication
Gene Expression Regulation, Neoplastic
Genetic Association Studies
Genetic Predisposition to Disease
Genomic Instability
Humans
MicroRNAs
/ genetics
Neoplasms
/ genetics
Recombinational DNA Repair
Synthetic Lethal Mutations
Translocation, Genetic
DNA repair
microRNA
oncogenesis
replication fork
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
27 08 2019
27 08 2019
Historique:
pubmed:
10
8
2019
medline:
31
3
2020
entrez:
10
8
2019
Statut:
ppublish
Résumé
Defects in DNA repair give rise to genomic instability, leading to neoplasia. Cancer cells defective in one DNA repair pathway can become reliant on remaining repair pathways for survival and proliferation. This attribute of cancer cells can be exploited therapeutically, by inhibiting the remaining repair pathway, a process termed synthetic lethality. This process underlies the mechanism of the Poly-ADP ribose polymerase-1 (PARP1) inhibitors in clinical use, which target BRCA1 deficient cancers, which is indispensable for homologous recombination (HR) DNA repair. HR is the major repair pathway for stressed replication forks, but when BRCA1 is deficient, stressed forks are repaired by back-up pathways such as alternative nonhomologous end-joining (aNHEJ). Unlike HR, aNHEJ is nonconservative, and can mediate chromosomal translocations. In this study we have found that miR223-3p decreases expression of PARP1, CtIP, and Pso4, each of which are aNHEJ components. In most cells, high levels of microRNA (miR) 223-3p repress aNHEJ, decreasing the risk of chromosomal translocations. Deletion of the miR223 locus in mice increases PARP1 levels in hematopoietic cells and enhances their risk of unprovoked chromosomal translocations. We also discovered that cancer cells deficient in BRCA1 or its obligate partner BRCA1-Associated Protein-1 (BAP1) routinely repress miR223-3p to permit repair of stressed replication forks via aNHEJ. Reconstituting the expression of miR223-3p in BRCA1- and BAP1-deficient cancer cells results in reduced repair of stressed replication forks and synthetic lethality. Thus, miR223-3p is a negative regulator of the aNHEJ DNA repair and represents a therapeutic pathway for BRCA1- or BAP1-deficient cancers.
Identifiants
pubmed: 31395736
pii: 1903150116
doi: 10.1073/pnas.1903150116
pmc: PMC6717293
doi:
Substances chimiques
3' Untranslated Regions
0
BRCA1 Protein
0
BRCA1 protein, human
0
MIRN223 microRNA, human
0
MicroRNAs
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
17438-17443Subventions
Organisme : NCI NIH HHS
ID : R01 CA197796
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM109645
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA205224
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA220123
Pays : United States
Organisme : NIEHS NIH HHS
ID : R01 ES007061
Pays : United States
Commentaires et corrections
Type : ErratumIn
Informations de copyright
Copyright © 2019 the Author(s). Published by PNAS.
Déclaration de conflit d'intérêts
Conflict of interest statement: R.H. has equity in Dialectic Therapeutics, which holds a licensing agreement for use of miR223-3p as a cancer therapeutic agent.
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