KU70 Binding Protein 5 (KUB5), A Novel Factor in DNA Double Strand Break Repair and Radio-Resistance in Human Breast Cancer

DNA double strand breaks (DSBs) are considered both mutagenic and carcinogenic if left un-repaired resulting in genomic instability and ultimately cancer. There are two main pathways for DSB repair: homologous recombination (HR) and non-homologous end joining (NHEJ). Defects in DSB repair have already been associated with breast cancer formation and increased breast cancer risk. Breast cancer susceptibility genes, BRCA1 and BRCA2 are largely thought to be involved with HR while LIG4, XRCC4, and Ku70 are linked to NHEJ. Deficiencies in any one of these genes can predispose individuals to breast cancer. In addition to predisposition to breast cancer, altered DNA repair processes can influence chemo- and radiotherapy efficacy by creating resistance to therapy. To study NHEJ further, our laboratory has identified a novel Ku70 binding protein #5 (KUB5) by a yeast two-hybrid screen using Ku70 as bait. Loss of RTT103, a putative yeast homolog of KUB5, resulted in increased sensitivity to IR, similar to that observed in hdf1-deletion yeast, the yeast homolog of Ku70. Results also show that RTT103-deletion yeast are deficient in repairing blunt and non-compatible DNA ends and re-expression of hKub5 can correct the IR-sensitivity and DNA repair deficiency of these deficient yeast demonstrating a strong functional model for human KUB5 function in yeast.
Analyses of breast cancer cell lines for their KUB5 protein expression yielded a strong correlation between KUB5 protein level and sensitivity to DNA damage. These data strongly suggests that KUB5 is a novel repair factor involved in NHEJ and endogenous over-expression of KUB5 plays a role in chemotherapeutic and/or radio-therapeutic resistance via increasing the capacity to facilitate NHEJ repair of DSBs in breast cancer cells.