A novel role of RECQL5, a DNA repair protein in mitochondrial dynamics associated radio-resistance in cancer

Clinically radiotherapy is successfully used for the treatment of different types of cancer. However, the clinical outcomes are refractory due to de novo and acquired radio-resistance in cancers. It is essential to understand the molecular mechanism (s) of radio-resistance of cancer for improving the clinical outcomes of radiotherapy. The most important target of ionizing radiation is DNA and repair of IR-induced DNA damages are extensively reported to be associated with radio-resistance of cancer. In recent past, an emerging role of mitochondria and metabolism is advocated in radio-resistance of cancer. However, the precise mechanism of regulation of mitochondrial dynamics and its role in radio-resistance is not yet known. RECQL helicase family proteins (RECQL1, BLM, WRN, RECQL4 and RECQL5) play crucial role in various DNA repair process (BER, NER, NHEJ and HRR). We and others have reported that RECQL1, BLM and WRN deficient cells show marginal or no sensitivity towards IR treatment. Interestingly, we observed a novel phenomenon that RECQL5 deficient cancers are radio-resistant in nature. Although, homologous recombination repair (HRR) is hyper-activated in RECQL5-deficient cancer cells, the kinetics of repair of IR induced DSBs are found to be grossly unaffected. Interestingly, we found that residual unrepaired DSBs are almost similar in RECQL5-KO cancers cells and RECQL5-proficient cancers, suggesting differential nuclear DNA repair might not account for radio-resistance of RECQL5-deficient cancers. Intriguingly, RECQL5 deficiency led to significant changes in mitochondrial dynamics and stress induced mitochondrial hyperfusion phenotype (SIMH). A detailed role of RECQL5 in SIMH and mitophagy in radio-sensitivity will be presented in the conference. (author)