Base Excision Repair: Mechanisms and Impact in Biology, Disease, and Medicine

Abstract

Base excision repair (BER) corrects forms of oxidative, deamination, alkylation, and abasic single-base damage that appear to have minimal effects on the helix. Since its discovery in 1974, the field has grown in several facets: mechanisms, biology and physiology, understanding deficiencies and human disease, and using BER genes as potential inhibitory targets to develop therapeutics. Within its segregation of short nucleotide (SN-) and long patch (LP-), there are currently six known global mechanisms, with emerging work in transcription- and replication-associated BER. Knockouts (KOs) of BER genes in mouse models showed that single glycosylase knockout had minimal phenotypic impact, but the effects were clearly seen in double knockouts. However, KOs of downstream enzymes showed critical impact on the health and survival of mice. BER gene deficiency contributes to cancer, inflammation, aging, and neurodegenerative disorders. Medicinal targets are being developed for single or combinatorial therapies, but only PARP and APE1 have yet to reach the clinical stage.

Keywords: 5′-Gap; APE1; NEIL1/2; OGG1; PARP; PNKP; POL β; RECQ1; XPF-ERCC1; XRCC1; base excision repair (BER); nucleotide incision repair (NIR); replication-associated; transcription-associated.

Figure 1

Timeline highlighting the discovery of various BER enzymes and pathways. References for the events in the figure are as follows: Lindahl, 1974 [8]; Friedberg, 2015 [9]; Krokan and Bjoras 2013, [10]; Pascucci et. al., 1999 [11]; Matsumoto et. al., 1994 [12]; Dantzer et. al., 2000 [13]; Woodrick et. al., 2017 [15]; Prasad et. al., 2001 [16]; Ischenko and Saparbaev, 2002 [17]; Liu et. al., 2005 [18]; Sukhanova et. al., 2010 [19]; Banerjee et. al., 2011 [20]; Hegde et. al., 2013 [21]. The figure was generated using Canva.com (accessed on 15 August 2023).

Figure 2

Global base excision repair (BER) mechanisms. Unlabeled DNA ends are either polymerase extendable clean 3′-OH groups or 5′-PO₄ groups that can be ligated. (i) Monofunctional glycosylase. (ii) Bifunctional glycosylase—β elimination. (iii) Bifunctional glycosylase—β, δ-elimination. (a) Short-Nucleotide BER (SN-BER). (b–e) Long-Patch BER (LP-BER). (b) Hit and Run. (c) Polymerase Switch. (d) Non-Polymerase Switch. (e) 5′-Gap. (f) Short-Patch Nucleotide Incision Repair (NIR). Genes with [] sign are target BER inhibitors. The figure was generated using Biorender.com (accessed on 20 August 2023).

Figure 3

Proposed transcription-associated BER mechanism.