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Review
. 2012:110:123-53.
doi: 10.1016/B978-0-12-387665-2.00006-7.

Oxidized base damage and single-strand break repair in mammalian genomes: role of disordered regions and posttranslational modifications in early enzymes

Muralidhar L Hegde  1 , Tadahide Izumi, Sankar Mitra
Affiliations
Review

Oxidized base damage and single-strand break repair in mammalian genomes: role of disordered regions and posttranslational modifications in early enzymes

Muralidhar L Hegde et al. Prog Mol Biol Transl Sci. 2012.

Abstract

Oxidative genome damage induced by reactive oxygen species includes oxidized bases, abasic (AP) sites, and single-strand breaks, all of which are repaired via the evolutionarily conserved base excision repair/single-strand break repair (BER/SSBR) pathway. BER/SSBR in mammalian cells is complex, with preferred and backup sub-pathways, and is linked to genome replication and transcription. The early BER/SSBR enzymes, namely, DNA glycosylases (DGs) and the end-processing proteins such as abasic endonuclease 1 (APE1), form complexes with downstream repair (and other noncanonical) proteins via pairwise interactions. Furthermore, a unique feature of mammalian early BER/SSBR enzymes is the presence of a disordered terminal extension that is absent in their Escherichia coli prototypes. These nonconserved segments usually contain organelle-targeting signals, common interaction interfaces, and sites of posttranslational modifications that may be involved in regulating their repair function including lesion scanning. Finally, the linkage of BER/SSBR deficiency to cancer, aging, and human neurodegenerative diseases, and therapeutic targeting of BER/SSBR are discussed.

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Figures

Fig. 1
Fig. 1
Schematic representation of mammalian BER/SSBR pathways for repair of oxidized bases, AP sites, and SSBs. The BER and SSBR pathways converge at the end-processing step. The gap-filling step may involve synthesis of 1 nt (SN-BER/SSBR) by Polβ or 2–8 nt (LP-BER/SSBR) by Polδ/ε or Polβ in collaboration with FEN-1. Other details are in the text.
Fig. 2
Fig. 2
Disordered terminal extensions in human (and other mammalian) early BER/SSBR proteins that are absent in their E. coli prototypes (not drawn to scale). In many cases, disordered segments were deleted for X-ray crystallographic structure analysis, which are consistent with PONDR prediction.,
See this image and copyright information in PMC

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