A 30-year-old woman with a family history of early-onset breast and ovarian cancer undergoes genetic testing. She is found to carry a BRCA1 pathogenic variant. BRCA1 protein functions in DNA repair primarily through:
- A Nucleotide excision repair (NER) of UV-induced bulky adducts via BRCA1 interaction with XPA and RPA
- B Base excision repair (BER) of oxidative DNA lesions via BRCA1 interaction with PARP1
- C Homologous recombination (HR) repair of double-strand breaks (DSBs): BRCA1 forms the BRCA1-BARD1 heterodimer that promotes end resection and recruits RAD51 for strand invasion and template-directed repair ✓
- D Mismatch repair (MMR) of replication errors via BRCA1 interaction with MLH1 and MSH2
Explanation
BRCA1 functions as a critical component of homologous recombination (HR) repair of DNA double-strand breaks. BRCA1 forms a constitutive heterodimer with BARD1 (BRCA1-associated RING domain 1) that possesses E3 ubiquitin ligase activity and participates in recruiting the MRN complex and CtIP for 5'-to-3' end resection at DSBs. The resulting 3' single-stranded overhangs are coated by RPA, which is replaced by RAD51 (facilitated by BRCA2 and PALB2), enabling RAD51-mediated strand invasion and error-free template-directed repair. Loss of BRCA1 forces repair into the error-prone NHEJ pathway, causing chromosomal instability and tumorigenesis. The BER-PARP1 connection is the basis of synthetic lethality between PARP inhibitors and BRCA1/2 loss.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.