Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA.
Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19111, USA.
Nat Commun. 2019 Dec 11;10(1):5661. doi: 10.1038/s41467-019-13530-6.
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.
BRCA1 突变型癌对 PARP 抑制剂（PARPi）治疗敏感；然而，耐药性会出现。BRCA1 BRCT 结构域突变蛋白不能正确折叠，并且容易受到蛋白酶体降解，从而导致 PARPi 敏感性。在这项研究中，我们表明，具有高度破坏性 BRCT 结构域突变的细胞系和患者来源的肿瘤具有可检测到的 BRCA1 蛋白表达，并能够在 PARPi 的存在下增殖。肽分析显示，化学抗性癌症含有 BRCA1 内含子 15 编码的残基。从机制上讲，BRCT 结构域突变的癌症在内含子 15 内或附近具有 BRCA1 基因断裂点；产生部分基因重复、倒位和易位，并在含有 BRCT 结构域的突变之前终止转录。BRCA1 BRCT 结构域缺陷蛋白异构体可避免突变诱导的蛋白酶体降解，支持同源依赖性 DNA 修复，并促进 PARPi 耐药性。总之，Alu 介导的 BRCA1 基因重排负责产生低功能蛋白，并且可能是 PARPi 耐药性的生物标志物。
