BRCA1 loses the ring but lords over resistance
Simon N. Powell
Simon N. Powell
Published July 25, 2016
Citation Information: J Clin Invest. 2016;126(8):2802-2804. https://doi.org/10.1172/JCI89209.
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Commentary

BRCA1 loses the ring but lords over resistance

Abstract

Germline breast cancer 1 (BRCA1) variants are associated with a high risk of breast and ovarian cancers. Many BRCA1-mediated cancers are initially responsive to platinum-based therapy; however, resistance commonly develops. The BRCA1185delAG mutation is common in the Ashkenazi Jewish population and has been thought to result in loss of function due to the introduction of a stop codon in the 5′ region of the BRCA1 transcript. Two studies in this issue of the JCI reveal that the BRCA1185delAG mutation results in the production of BRCA1 that lacks the N-terminal really interesting new gene (RING) domain. RING-less BRCA1 was shown to directly mediate chemoresistance, while maintaining some homologous recombination function. These results provide important insight into BRCA1 function and indicate that other truncated proteins could arise through similar alterations in codon usage.

Authors

Simon N. Powell

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Figure 1

Effects of the 185delAG mutation on BRCA1 function.

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Effects of the 185delAG mutation on BRCA1 function. (A) WT BRCA1 contain...
(A) WT BRCA1 contains a RING domain (red), a nuclear localization sequence (NLS, purple) and a functional C-terminal domain (BRCT, green). The WT protein has multiple functions, including DNA damage repair, maintenance of replication fidelity, tumor suppression, and support of embryonic growth. PTM, posttranslational modification. (B) In this issue of the JCI, two studies demonstrate alternative translation of BRCA1 mRNA at the Met-297 codon (bright green arrow) in genetically defined human cells and genetically engineered mouse cells. The 185delAG mutation was thought to result in a frameshift mutation with an early stop codon (red arrow); however, this mutation supports translation at the Met-297 site, but not at other putative in-frame methionine residues (gray arrows). The alternative protein lacks the RING domain and does not prevent embryonic lethality or tumor formation; however, this truncated protein does allow DNA repair by HR at approximately 50% of the activity of WT BRCA1. One explanation may be the distinct roles of BRCA1 in DNA damage repair and replication fidelity. Alternative explanations are possible and include transcriptional changes via chromatin PTMs.