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Tumbling down a different pathway to genetic instability
Haiwei H. Guo and Lawrence A. Loeb
Joseph Gottstein Cancer Research Laboratory, Department of Pathology, University of Washington, Seattle, Washington, USA
Address correspondence to: Lawrence A. Loeb, Department of Pathology, K-072 HSB, 1959 NE Pacific Street, University of Washington, Seattle, Washington 98195–7705, USA. Phone: (206) 543–6015; Fax: (206) 543-3967; E-mail: laloeb@u.washington.edu.
Find articles by Guo, H. in: JCI | PubMed | Google Scholar
Joseph Gottstein Cancer Research Laboratory, Department of Pathology, University of Washington, Seattle, Washington, USA
Address correspondence to: Lawrence A. Loeb, Department of Pathology, K-072 HSB, 1959 NE Pacific Street, University of Washington, Seattle, Washington 98195–7705, USA. Phone: (206) 543–6015; Fax: (206) 543-3967; E-mail: laloeb@u.washington.edu.
Find articles by Loeb, L. in: JCI | PubMed | Google Scholar
Published December 15, 2003 - More info
J Clin Invest. 2003;112(12):1793–1795. https://doi.org/10.1172/JCI20502.
© 2003 The American Society for Clinical Investigation
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DNA repair mechanisms: doing good and harm?
A provocative hypothesis has now emerged, in which DNA repair enzymes are no longer seen as guardians of the genome but instead go awry, fumble like “Keystone Cops,” and create unintended consequences in UC. The conceptual basis of this idea was introduced a decade ago, when Samson and Xiao first proposed and demonstrated that imbalanced base excision repair (BER) with broad substrate-specific 3-methyladenine DNA glycosylases could affect spontaneous mutation rates (8). While the mismatch repair pathway has frequently been the focus of MSI studies, in this issue of the JCI Hofseth and coworkers (9) instead considered the BER pathway, which includes the DNA repair enzymes 3-methyladenine DNA glycosylase (AAG) and apurinic/apyrimidinic endonuclease (APE1) (Figure 1). AAG removes a range of damaged bases, such as N3-methyladenine 1, N6-ethenoadenine, and hypoxanthine from DNA by hydrolyzing the glycosylic bond attaching the damaged base to the deoxyribose sugar. APE1 processes the resulting apurinic/apyrimidinic (AP) site by incising the phosphodiester backbone of DNA immediately 5′ to the baseless sugar, leaving a strand break with a normal 3′ hydroxyl that can prime repair synthesis by DNA polymerases. APE1 can also process modified AP sites resulting from oxidative damage to deoxyribose. The authors theorize that the chronic inflammation in UC causes adaptive increases in AAG and APE1 levels, which paradoxically enhance MSI in affected tissues, suggesting that these enzymes, which normally facilitate DNA repair, are instead causing mutations.
Figure 1Schematic illustrating base excision repair by a simple DNA glycosylase, AAG, which removes the damaged base but does not cleave the DNA backbone. APE1 makes a 5′ nick in the backbone. In the short-patch pathway (left), polβ synthesizes one nucleotide and removes the 5′-terminal baseless sugar via its lyase activity, supported by the scaffolding protein XRCC1. DNA ligase III seals the remaining nick. In the long-patch pathway (rick. Until the final ligation step is completed, toxic and mutagenic DNA repair intermediates, such as AP sites and single-stranded breaks, are still present in the genome.
The authors proceeded by showing that there are significantly greater amounts of AAG and APE1 proteins in active inflamed areas of UC lesions than in noninflamed areas from the same patient; and that AAG and APE1 enzymatic activities are positively correlated with increased inflammation, as measured by the level of CD68, a monocyte and macrophage marker (Figure 2) (9). Furthermore, AAG and APE1 activities were positively correlated with the degree of MSI instability of the UC colon tissue. However, guilt by statistically significant association should not persuade a competent jury of causality. So the authors provide more definitive evidence. Overexpression of AAG alone or in addition to APE1 in mismatch repair–proficient yeast produced increases of as much as 30-fold in –1 and 6-fold in +1 frameshift mutations. Furthermore, co-overexpression of AAG and APE1 in the human erythroleukemic cell line K562 produced instability at four of seven microsatellite loci examined, whereas no MSI was detected in the vector-only control. Together, these results suggest that adaptive increases in the BER enzymes AAG and APE1 contribute to MSI in UC.
Figure 2Schematic illustrating the proposed mechanism of how chronic inflammation may induce microsatellite instability in ulcerative colitis. Among the factors released by inflammatory cells in ulcerative colitis are proinflammatory cytokines, ROS, and NO. Hofseth et al. (9) propose and provide evidence for inflammation-associated increases in the levels of the DNA repair enzymes AAG and APE1, which in turn produce instability at microsatellite sequences in various types of cells in the affected tissue (shown here as a colonic crypt stem cell). The exact mechanism through which AAG and APE1 produce MSI remains to be elucidated, but it may be related to imbalances in the components of the base excision repair pathway and the accumulation of mutagenic repair intermediates.
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