Base excision repair: a critical player in many games

Abstract

This perspective reviews the many dimensions of base excision repair from a 10,000 foot vantage point and provides one person's view on where the field is headed. Enzyme function is considered under the lens of X-ray diffraction and single molecule studies. Base excision repair in chromatin and telomeres, regulation of expression and the role of posttranslational modifications are also discussed in the context of enzyme activities, cellular localization and interacting partners. The specialized roles that base excision repair play in transcriptional activation by active demethylation and targeted oxidation as well as how base excision repair functions in the immune processes of somatic hypermutation and class switch recombination and its possible involvement in retroviral infection are also discussed. Finally the complexities of oxidative damage and its repair and its link to neurodegenerative disorders, as well as the role of base excision repair as a tumor suppressor are examined in the context of damage, repair and aging. By outlining the many base excision repair-related mysteries that have yet to be unraveled, hopefully this perspective will stimulate further interest in the field.

Keywords: AP endonuclease; Aging; BER and transcriptional regulation; BER crosspathways; BER in the immune system; BER subpathways; Base excision repair; Cancer; DNA glycosylase search; DNA glycosylases; Neurodegenerative diseases; Repair enzyme structures; Repair in chromatin; Repair in telomeres.

Fig. 1

This cartoon was inspired by the 1996 Failla lecture delivered by the Author to the Radiation Research Society discussing base excision repair of radiation-induced free radical damage. The model of the baseball diamond based on Abbot and Costello’s skit “Who’s on First, What’s on Second, I Don’t Know’s on Third,” was used to describe the activities of the four sets of BER enzymes, the glycosylases (first base), AP endonucleases (second base), DNA polymerases (third base), and ligases (home plate), which was about the extent of what was known at the time. This cartoon jumps almost two decades to display in outline form our current knowledge of BER processing which has definitely come from the minor to the major leagues.