Co-depletion of BRCA2 and POLQ by siRNA markedly increased sensitivity of A549/DR cells to cisplatin, which was accompanied with impairment of double strand breaks (DSBs) repair reflected by prominent cell cycle checkpoint response, increased chromosomal aberrations and persistent colocalization of p-ATM and 53BP1 foci induced by cisplatin.
Since un- or misrepaired DSB lead to chromosomal anomalies which may promote the development of breast cancer, we have studied the potential of mammography X-rays for immediate and delayed induction of chromosomal anomalies in human primary fibroblasts from BRCA1 and BRCA2 mutation carriers.
We show that HR defective cells (BRCA2, Rad51D and XRCC3 mutants) are dramatically more sensitive to MMS-induced DNA damage as measured by colony formation, apoptosis and chromosomal aberrations, while NHEJ defective cells (Ku80 and DNA-PK(CS) mutants) are only mildly sensitive to the killing, apoptosis-inducing and clastogenic effects of MMS.
BRCA1- and BRCA2-mutated breast cancers are associated with increased amounts of chromosomal aberrations, presumably due their functions in genome repair.
BRCA2 protein interacts directly with the RAD51 recombinase and regulates recombination-mediated DSB repair, accounting for the high levels of spontaneous chromosomal aberrations seen in BRCA2-defective cells.
The high level of spontaneous chromosomal aberrations in Brca2 mutant cells was largely suppressed by the BRC-RPA fusion proteins, supporting the notion that the primary role of BRCA2 in maintaining genomic integrity is in HDR, specifically to deliver Rad51 to ssDNA.
Chromosomal aberrations in breast tumors from BRCA1 and BRCA2 germ-line mutation carriers are considerably more frequent than what is seen in sporadic breast tumors.
Familial ovarian tumors exhibit a significantly higher number of chromosomal aberrations and genomic imbalances and nonrandom genetic changes were characterized in the BRCA1 and BRCA2 groups.
Breast tumours from BRCA1 and BRCA2 mutation carriers are genetically instable and display specific patterns of chromosomal aberrations, suggestive of distinct genetic pathways in tumour progression.
We propose that the coexistence of this rare chromosomal abnormality with BRCA2 mutation may be augmenting the risk of male breast cancer conferred by the BRCA2 mutation.