DNA polymerase Family X: Function, structure, and cellular roles

Yamtich, Jennifer; Sweasy, Joann B.

doi:10.1016/j.bbapap.2009.07.008

Cited by 133 publications

(154 citation statements)

References 178 publications

(258 reference statements)

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“…As a key enzyme involved in DNA base excision repair, pol ␤ has been implicated in CAG repeat expansion during the repair of oxidative damage that occurs within CAG repeats (15). Previous studies have also shown that pol ␤ can bypass a number of different types of lesions in the template strand, including cisplatin adducts, cyclobutanol pyrimidine dimers, and 6 -4 photoproducts (34). We demonstrate here that pol ␤ can also "bypass" a (CAG) n / (CTG) n hairpin lesion, but the "bypass" in our study occurs in the primer strand, leading to expansion of the repeats.…”

Section: Discussionmentioning

confidence: 99%

Coordinated Processing of 3′ Slipped (CAG)n/(CTG)n Hairpins by DNA Polymerases β and δ Preferentially Induces Repeat Expansions

Chan

Guo

Zhang

et al. 2013

Journal of Biological Chemistry

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Background: Expansion of CAG/CTG repeats causes familial neurological disorders, but the molecular basis is unknown. Results: DNA polymerases ␤ and ␦ effectively incorporate nucleotides to a CAG/CTG hairpin primer, leading to hairpin retention. Conclusion: Coordinated actions by polymerases ␤ and ␦ on hairpin primers during DNA synthesis promotes CAG/CTG repeat expansions. Significance: The work discovers a novel mechanism for CAG/CTG repeat expansions.

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Section: Discussionmentioning

confidence: 99%

Coordinated Processing of 3′ Slipped (CAG)n/(CTG)n Hairpins by DNA Polymerases β and δ Preferentially Induces Repeat Expansions

Chan

Guo

Zhang

et al. 2013

Journal of Biological Chemistry

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“…Interestingly, some types of DNA damage, such as cisplatin-induced lesions, are repaired more slowly in human cells than in chimpanzee cells, which is consistent with the hypothesis of downregulation of repair in humans (Weis et al 2008). Pol b is capable of error-prone bypassing of several types of DNA lesions, including 8-oxo-7,8-dihydrodeoxyguanine, cisplatininduced lesions, and UV-induced lesions (Yamtich and Sweasy 2009). Overexpression of Pol b is associated with an increase in the mutation rate (Chan et al 2007).…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Pol b is a 335-amino-acid, 39-kDa polymerase encoded by the POLB locus after the splicing of its 14 constitutive exons (Uchiyama et al 2009;Yamtich and Sweasy 2009). Pol b is a member of the X-family of DNA repair polymerases, plays a key role in base excision DNA repair, and its absence leads to sensitivity to methylating agents (Yamtich and Sweasy 2009). POLB is believed to have evolved after the protostome-deuterostome branching, being essential in vertebrates and expressed in all cell types (Uchiyama et al 2009;Yamtich and Sweasy 2009).…”

Section: Introductionmentioning

confidence: 99%

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The adaptive significance of unproductive alternative splicing in primates

Skandalis

Frampton²,

Seger³

et al. 2010

RNA

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Alternative gene splicing is pervasive in metazoa, particularly in humans, where the majority of genes generate splice variant transcripts. Characterizing the biological significance of alternative transcripts is methodologically difficult since it is impractical to assess thousands of splice variants as to whether they actually encode proteins, whether these proteins are functional, or whether transcripts have a function independent of protein synthesis. Consequently, to elucidate the functional significance of splice variants and to investigate mechanisms underlying the fidelity of mRNA splicing, we used an indirect approach based on analyzing the evolutionary conservation of splice variants among species. Using DNA polymerase b as an indicator locus, we cloned and characterized the types and frequencies of transcripts generated in primary cell lines of five primate species. Overall, we found that in addition to the canonical DNA polymerase b transcript, there were 25 alternative transcripts generated, most containing premature terminating codons. We used a statistical method borrowed from community ecology to show that there is significant diversity and little conservation in alternative splicing patterns among species, despite high sequence similarity in the underlying genomic (exonic) sequences. However, the frequency of alternative splicing at this locus correlates well with life history parameters such as the maximal longevity of each species, indicating that the alternative splicing of unproductive splice variants may have adaptive significance, even if the specific RNA transcripts themselves have no function. These results demonstrate the validity of the phylogenetic conservation approach in elucidating the biological significance of alternative splicing.

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“…Moreover, a systematic and thorough analysis of the roles of residues remote from the active site in DNA polymerase b has identified residues that are important for nucleotide selection and template alignment [Yamtich and Sweasy, 2010]. As one example, a triad of residues Arg333 Glu316 Arg182 in the fingers domain of pol b may disrupt packing of side chains in the hinge region and therefore alter the conformational change required for efficient DNA replication [Murphy et al, 2011].…”

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confidence: 99%

Effects of non‐catalytic, distal amino acid residues on activity of E. coli DinB (DNA polymerase IV)

Walsh

Parasuram

Rajput

et al. 2012

Environ and Mol Mutagen

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DinB is one of two Y family polymerases in E. coli and is involved in copying damaged DNA. DinB is specialized to bypass deoxyguanosine adducts that occur at the N 2 position, with its cognate lesion being the furfuryl adduct. Active site residues have been identified that make contact with the substrate and carry out deoxynucleotide triphosphate (dNTP) addition to the growing DNA strand. In DNA polymerases, these include negatively charged aspartate and glutamate residues (D8, D103, and E104 in E. coli DNA polymerase IV DinB). These residues position the essential magnesium ions correctly to facilitate nucleophilic attack by the primer hydroxyl group on the a-phosphate group of the incoming dNTP. To study the contribution of DinB residues to lesion bypass, the computational methods THEMATICS and POOL were employed. These methods correctly predict the known active site residues, as well as other residues known to be important for activity. In addition, these methods predict other residues involved in substrate binding as well as more remote residues. DinB variants with mutations at the predicted positions were constructed and assayed for bypass of the N 2 -furfuryl-dG lesion. We find a wide range of effects of predicted residues, including some mutations that abolish damage bypass. Moreover, most of the DinB variants constructed are unable to carry out the extension step of lesion bypass. The use of computational prediction methods represents another tool that will lead to a more complete understanding of translesion DNA synthesis. Environ. Mol. Mutagen. 53:766-776, 2012. V V C 2012 Wiley Periodicals, Inc.

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DNA polymerase Family X: Function, structure, and cellular roles

Cited by 133 publications

References 178 publications

Coordinated Processing of 3′ Slipped (CAG)n/(CTG)n Hairpins by DNA Polymerases β and δ Preferentially Induces Repeat Expansions

Coordinated Processing of 3′ Slipped (CAG)n/(CTG)n Hairpins by DNA Polymerases β and δ Preferentially Induces Repeat Expansions

The adaptive significance of unproductive alternative splicing in primates

Effects of non‐catalytic, distal amino acid residues on activity of E. coli DinB (DNA polymerase IV)

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