Cellular role of yeast Apn1 apurinic endonuclease/3'-diesterase: repair of oxidative and alkylation DNA damage and control of spontaneous mutation.

Ramotar, Dindial; Popoff, S C; Gralla, E B; Demple, Bruce

doi:10.1128/mcb.11.9.4537

Cited by 203 publications

(193 citation statements)

References 37 publications

Supporting

Mentioning

173

Contrasting

Unclassified

Order By: Relevance

“…In yeast, it was previously demonstrated that a deletion of the N-glycosylase NTG1, or the AP endonuclease APN1, leads to a decrease in mitochondrial mutations as measured by rates of erythromycin resistance, suggesting that the actions of Ntg1p and Apn1p create mutagenic intermediates in mtDNA during repair (Phadnis et al 2006). This stands in contrast to the increases seen for nuclear DNA mutation rates in the presence of these deletion alleles, indicating that it is not always possible to extrapolate the mitochondrial function of BER proteins on the basis of their nuclear functions, thus making mitochondrial-specific studies necessary (Ramotar et al 1991(Ramotar et al , 1993Alseth et al 1999;Bennett 1999). In addition, there are likely to be mitochondrialspecific players in the pathway.…”

Section: Epletion Of Mitochondrial Function Has Beencontrasting

confidence: 46%

“…Deletion of APN1 has been reported to increase nuclear mutation rates 2-to 12-fold, and reported effects of NTG1 deletion range from insignificant to 40-fold over wild-type levels (Ramotar et al 1991(Ramotar et al , 1993Bennett 1999;Hanna et al 2004;Doudican et al 2005). To determine how mtDNA is affected by these deletions, we assayed for spontaneous resistance to Ery R .…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Evidence That Msh1p Plays Multiple Roles in Mitochondrial Base Excision Repair

2009

View full text Add to dashboard Cite

Mitochondrial DNA is thought to be especially prone to oxidative damage by reactive oxygen species generated through electron transport during cellular respiration. This damage is mitigated primarily by the base excision repair (BER) pathway, one of the few DNA repair pathways with confirmed activity on mitochondrial DNA. Through genetic epistasis analysis of the yeast Saccharomyces cerevisiae, we examined the genetic interaction between each of the BER proteins previously shown to localize to the mitochondria. In addition, we describe a series of genetic interactions between BER components and the MutS homolog MSH1, a respiration-essential gene. We show that, in addition to their variable effects on mitochondrial function, mutant msh1 alleles conferring partial function interact genetically at different points in mitochondrial BER. In addition to this separation of function, we also found that the role of Msh1p in BER is unlikely to be involved in the avoidance of large-scale deletions and rearrangements.

show abstract

Section: Epletion Of Mitochondrial Function Has Beencontrasting

confidence: 46%

Section: Resultsmentioning

confidence: 99%

Evidence That Msh1p Plays Multiple Roles in Mitochondrial Base Excision Repair

2009

View full text Add to dashboard Cite

show abstract

“…In addition to Apn1, S. cerevisiae contains a second enzyme with AP endonuclease activity, Apn2. Although Apn1 accounts for Ͼ90% of the AP endonuclease activity in yeast (31), the sensitivity of an apn1 apn2 double mutant to agents that induce depurination is substantially greater than that of either single mutant (32,33). This observation suggests that, despite differences in their abundance and͞or catalytic efficiencies, the two enzymes function somewhat redundantly.…”

Section: Resultsmentioning

confidence: 69%

Repair of topoisomerase I covalent complexes in the absence of the tyrosyl-DNA phosphodiesterase Tdp1

Liu

Pouliot

Nash

2002

Proc. Natl. Acad. Sci. U.S.A.

161

175

View full text Add to dashboard Cite

Accidental or drug-induced interruption of the breakage and reunion cycle of eukaryotic topoisomerase I (Top1) yields complexes in which the active site tyrosine of the enzyme is covalently linked to the 3 end of broken DNA. The enzyme tyrosyl-DNA phosphodiesterase (Tdp1) hydrolyzes this protein-DNA link and thus functions in the repair of covalent complexes, but genetic studies in yeast show that alternative pathways of repair exist. Here, we have evaluated candidate genes for enzymes that might act in parallel to Tdp1 so as to generate free ends of DNA. Despite finding that the yeast Apn1 protein has a Tdp1-like biochemical activity, genetic inactivation of all known yeast apurinic endonucleases does not increase the sensitivity of a tdp1 mutant to direct induction of Top1 damage. In contrast, assays of growth in the presence of the Top1 poison camptothecin (CPT) indicate that the structure-specific nucleases dependent on RAD1 and MUS81 can contribute independently of TDP1 to repair, presumably by cutting off a segment of DNA along with the topoisomerase. However, cells in which all three enzymes are genetically inactivated are not as sensitive to the lethal effects of CPT as are cells defective in double-strand break repair. We show that the MRE11 gene is even more critical than the RAD52 gene for double-strand break repair of CPT lesions, and comparison of an mre11 mutant with a tdp1 rad1 mus81 triple mutant demonstrates that other enzymes complementary to Tdp1 remain to be discovered.

show abstract

“…The only significant difference identified between Apn1 and endonuclease IV was the presence in the yeast protein of a nuclear targeting signal in a short C-terminal extension (Ramotar et al, 1993). Eventually, the construction of Apn1-deficient yeast confirmed the role of the enzyme in the repair of oxidative damage, presumably including the excision of 3'-PG at oxidative strand breaks (Ramotar et al, 1991).…”

Section: The Biology Of Oasmentioning

confidence: 74%