Identification of base excision repair enzymes to clarify their biological significance in relation to aging in C. elegans

Abstract

Reactive oxygen species (ROS) are generated in living cells during normal cellular metabolism as well as by exogenous stimuli such as ionizing radiation and various chemical oxidants. DNA carrying vital genetic information of cells constantly suffers from spontaneous oxidation by ROS. ROS produce a wide variety of oxidative damage to DNA, including various types of base modifications. Oxidatively damaged bases in DNA cause deleterious effects such as mutation, cell death and aging. Recently, relationship between oxidative damage to DNA and aging has been suggested, but the molecular mechanisms remain unsolved. Base excision repair (BER) is the main pathway to repair oxidative base damage. DNA glycosylase and AP endonuclease are essential to maintain genome stability by excising various types of DNA lesions. It is necessary to examine whether the mutation in the BER enzymes affects the life span of cells and organisms. The nematode C. elegans is a useful model organism for studying aging because its lifespan can be determined easily and quickly. However, there are little reports on BER enzymes of C. elegans. In this study, we identified and analyzed DNA glycosylases and AP endonucleases of C. elegans. CeNTH- and Ung-1-deficient C. elegans showed no significant difference in lifespan compared to the wild type N2. The results suggested the existence of other DNA glycosylase(s) that functions to repair oxidized pyrimidines and uracil in DNA. That is, the deletion of one DNA glycosylase could be complemented by other DNA glycosylases that are able to excise the same types of damaged bases. In addition to BER enzymes, we are studying roles of the OXR protein in relation to aging in C. elegans.