Sanitization of nucleotides via autophagy for DNA repair

• Main Authors: Tung Chao, 趙彤
• Other Authors: Zee-Fen Chang
• Format: Others
• Language: en_US
• Published: 2015
• Online Access: http://ndltd.ncl.edu.tw/handle/14293894266348107329

碩士 === 國立陽明大學 === 生化暨分子生物研究所 === 103 === Recent studies have shown autophagy as a part of DNA damage response. In this report, I showed that inhibition of autophagy increases oxidative DNA damage with a concurrent elevation of ROS in tumor cells during recovery from different genotoxic insults, leading to deficiencies in DNA repair and cell survival. These effects were reversed by exogenous supplementation of nucleosides and anti-oxidant. Overexpression of MTH1, an enzyme that hydrolyzes oxidized nucleotides, also rescued DNA repair when autophagy was suppressed, suggesting the relation of autophagy with sanitization control of nucleotides in DNA repair. By induction of a restriction enzyme in the nuclei to cause specific DNA lesions in nuclear genome, I demonstrated that the combination of mitochondrial damage with autophagy inhibition interfered with DNA repair in nuclear genome. My data suggest that mitochondria damage after genotoxic insult in tumor cells requires autophagy to prevent too much ROS production and to give sanitized nucleotides for DNA repair. As a contrast, in non-tumorigenic cells, autophagy inhibition did not cause a significant ROS induction after genotoxic insult, thereby having no effect on DNA repair. Thus, the differential mitochondrial response to genotoxic insult determines the mitophagy requirement for the quality control of nucleotides in DNA repair.