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Wang Y , Bernhardy AJ , Nacson J , Krais JJ , Tan YF , Nicolas E , Radke MR , Handorf E , Llop-Guevara A , Balmana J , Swisher EM , Serra V , Peri S , Johnson N
BRCA1 intronic Alu elements drive gene rearrangements and PARP inhibitor resistance
Nat Commun. 2019 Dec 11;10(1) :5661
PMID: 31827092    PMCID: PMC6906494   
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Abstract
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.
Notes
2041-1723 Wang, Yifan Bernhardy, Andrea J Nacson, Joseph Krais, John J ORCID: http://orcid.org/0000-0002-3916-3435 Tan, Yin-Fei Nicolas, Emmanuelle Radke, Marc R Handorf, Elizabeth Llop-Guevara, Alba Balmana, Judith Swisher, Elizabeth M Serra, Violeta ORCID: http://orcid.org/0000-0001-6620-1065 Peri, Suraj Johnson, Neil P50 CA083638/CA/NCI NIH HHS/United States R01CA214799/Center for Strategic Scientific Initiatives, National Cancer Institute (NCI Center for Strategic Scientific Initiatives) OC130212/U.S. Department of Defense (United States Department of Defense) Journal Article England Nat Commun. 2019 Dec 11;10(1):5661. doi: 10.1038/s41467-019-13530-6.