Next-generation sequencing (NGS) of a familial breast cancer gene panel shows a variant in BRCA1: c.5266dupC (also designated 5382insC), a frameshift mutation creating a premature stop codon. This variant is common among Ashkenazi Jewish populations. The resulting truncated BRCA1 protein lacks the BRCT domain. The BRCT domain is essential for which specific DNA repair function?
- A Phosphopeptide binding to recruit repair factors to double-strand breaks at phosphorylated H2AX (gamma-H2AX) foci ✓
- B Recognition of single-strand breaks in base excision repair
- C E3 ubiquitin ligase activity required for PCNA ubiquitination during translesion synthesis
- D Catalytic helicase activity for unwinding DNA ahead of the repair machinery
Explanation
The BRCT (BRCA1 C-terminal) domain is a phosphoprotein-binding module that recognizes phosphoserine/phosphothreonine-containing peptides. After DNA double-strand breaks (DSBs), ATM/ATR kinases phosphorylate H2AX on Ser-139 (gamma-H2AX) at the break site. The BRCA1 BRCT domain binds phosphorylated Abraxas/BACH1 (BRIP1) and CtIP in the BRCA1-A and BRCA1-C complexes, respectively, recruiting BRCA1 to DSB repair foci. This recruitment is essential for coordinating homologous recombination (HR) repair of DSBs in S/G2 phases. Loss of the BRCT domain (as in 5382insC truncation) abolishes HR repair, causing genomic instability and susceptibility to breast/ovarian cancer. The BRCT domain is also present in other repair proteins (MDC1, 53BP1, XRCC1).
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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