Saccharomyces cerevisiae Apn1 mutation affecting stable protein expression mimics catalytic activity impairment: Implications for assessing DNA repair capacity in humans

Morris, Lydia P.; Degtyareva, Natalya; Sheppard, Clayton; Heyburn, Lanier; Ivanov, Andrey A.; Kow, Yoke W.; Doetsch, Paul W.

doi:10.1016/j.dnarep.2012.06.008

Cited by 4 publications

(1 citation statement)

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“…The catalytic amino acid substitution variant Apn1(D192G) was shown to bind DNA more efficiently than wild type (Jilani et al ., ). Recently, we used a mutagenesis screen approach to identify and characterize functional amino acid substitution variants of Apn1 (Morris et al ., ). We will use this approach in future studies to identify ‘strong binder’ variants of Apn1 to further characterize the genome‐wide occupancy.…”

Section: Discussionmentioning

confidence: 97%

Genome‐wide map of Apn1 binding sites under oxidative stress in Saccharomyces cerevisiae

Morris

Conley

Degtyareva

et al. 2017

Yeast

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The DNA is cells is continuously exposed to reactive oxygen species resulting in toxic and mutagenic DNA damage. Although the repair of oxidative DNA damage occurs primarily through the base excision repair (BER) pathway, the nucleotide excision repair (NER) pathway processes some of the same lesions. In addition, damage tolerance mechanisms, such as recombination and translesion synthesis, enable cells to tolerate oxidative DNA damage, especially when BER and NER capacities are exceeded. Thus, disruption of BER alone or disruption of BER and NER in Saccharomyces cerevisiae leads to increased mutations as well as large-scale genomic rearrangements. Previous studies demonstrated that a particular region of chromosome II is susceptible to chronic oxidative stress-induced chromosomal rearrangements, suggesting the existence of DNA damage and/or DNA repair hotspots. Here we investigated the relationship between oxidative damage and genomic instability utilizing chromatin immunoprecipitation combined with DNA microarray technology to profile DNA repair sites along yeast chromosomes under different oxidative stress conditions. We targeted the major yeast AP endonuclease Apn1 as a representative BER protein. Our results indicate that Apn1 target sequences are enriched for cytosine and guanine nucleotides. We predict that BER protects these sites in the genome because guanines and cytosines are thought to be especially susceptible to oxidative attack, thereby preventing large-scale genome destabilization from chronic accumulation of DNA damage. Information from our studies should provide insight into how regional deployment of oxidative DNA damage management systems along chromosomes protects against large-scale rearrangements.

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Section: Discussionmentioning

confidence: 97%