BRCA1 intronic Alu elements drive gene rearrangements and PARP inhibitor resistance.
Alu Elements
Animals
Antineoplastic Agents
/ administration & dosage
BRCA1 Protein
/ genetics
Breast Neoplasms
/ drug therapy
Chromosome Inversion
Drug Resistance, Neoplasm
Female
Gene Rearrangement
Humans
Introns
Mice
Mice, Nude
Poly(ADP-ribose) Polymerase Inhibitors
/ administration & dosage
Translocation, Genetic
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
11 12 2019
11 12 2019
Historique:
received:
16
03
2018
accepted:
14
11
2019
entrez:
13
12
2019
pubmed:
13
12
2019
medline:
12
3
2020
Statut:
epublish
Résumé
BRCA1 mutant carcinomas are sensitive to PARP inhibitor (PARPi) therapy; however, resistance arises. BRCA1 BRCT domain mutant proteins do not fold correctly and are subject to proteasomal degradation, resulting in PARPi sensitivity. In this study, we show that cell lines and patient-derived tumors, with highly disruptive BRCT domain mutations, have readily detectable BRCA1 protein expression, and are able to proliferate in the presence of PARPi. Peptide analyses reveal that chemo-resistant cancers contain residues encoded by BRCA1 intron 15. Mechanistically, cancers with BRCT domain mutations harbor BRCA1 gene breakpoints within or adjacent to Alu elements in intron 15; producing partial gene duplications, inversions and translocations, and terminating transcription prior to the mutation-containing BRCT domain. BRCA1 BRCT domain-deficient protein isoforms avoid mutation-induced proteasomal degradation, support homology-dependent DNA repair, and promote PARPi resistance. Taken together, Alu-mediated BRCA1 gene rearrangements are responsible for generating hypomorphic proteins, and may represent a biomarker of PARPi resistance.
Identifiants
pubmed: 31827092
doi: 10.1038/s41467-019-13530-6
pii: 10.1038/s41467-019-13530-6
pmc: PMC6906494
doi:
Substances chimiques
Antineoplastic Agents
0
BRCA1 Protein
0
BRCA1 protein, human
0
Poly(ADP-ribose) Polymerase Inhibitors
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
5661Subventions
Organisme : NCI NIH HHS
ID : R01 CA214799
Pays : United States
Organisme : Center for Strategic Scientific Initiatives, National Cancer Institute (NCI Center for Strategic Scientific Initiatives)
ID : R01CA214799
Pays : International
Organisme : NCI NIH HHS
ID : P50 CA083638
Pays : United States
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