UV-B Radiation Induces Epithelial Tumors in Mice Lacking DNA Polymerase η and Mesenchymal Tumors in Mice Deficient for DNA Polymerase ι

Ohkumo, Tsuyoshi; Kondo, Yuji; Yokoi, Masayuki; Tsukamoto, Tetsuya; Yamada, Ayumi; Sugimoto, Taiki; Kanao, Rie; Higashi, Youichirou; Kondoh, Hisato; Tatematsu, Masae; Masutani, Chikahide; Hanaoka, Fumio

doi:10.1128/mcb.01076-06

Cited by 106 publications

(89 citation statements)

References 74 publications

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“…cells) exhibited significant sensitivity to UV-C irradiation (Ohkumo et al 2006). We also showed that expression of human Polg (hPolg) or mouse Polg (mPolg) rescued the UV sensitivity of XP-V cells (Yamada et al 2000).…”

Section: Expression Of Mouse Polg Fully Complemented the Uv Sensitivimentioning

confidence: 79%

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Stalled Polη at its cognate substrate initiates an alternative translesion synthesis pathway via interaction with REV1

Ito¹,

Yokoi²,

Sakayoshi³

et al. 2012

Genes to Cells

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DNA polymerase g (Polg), whose gene mutation is responsible for the inherited disorder xeroderma pigmentosum variant (XP-V), carries out accurate and efficient translesion synthesis (TLS) across cyclobutane pyrimidine dimer (CPD). As Polg interacts with REV1, and REV1 interacts with other TLS polymerases including Poli, Polj and Polf, Polg may play a role in recruitment of these TLS polymerases at lesion site. But it is unclear whether UV sensitivity of XP-V patients is caused not only by defect of Polg activity but also by dysfunction of network between Polg and other TLS polymerases. Here, we examined whether the TLS polymerase network via Polg is important for replicative bypass of CPDs and DNA damage tolerance induced by UV in mouse cells. We observed that UV sensitivity of Polg-deficient mouse cells was moderately rescued by the expression of a catalytically inactive Polg. Moreover, this recovery of cellular UV sensitivity was mediated by the interaction between Polg and REV1. However, expression of the inactive mutant Polg was not able to suppress the incidence of UV-induced mutation observed in Polg-deficient cells. We propose the model that REV1 and Polj are involved in DNA damage tolerance via Polg-REV1 interaction when Polg fails to bypass its cognate substrates.

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Section: Expression Of Mouse Polg Fully Complemented the Uv Sensitivimentioning

confidence: 79%

“…Cell culture, transfection and UV exposure Polh ) ⁄ ) and Polh ) ⁄ ) Poli ) ⁄ ) MEF cells were as described (Ohkumo et al 2006). The…”

Section: Methodsmentioning

confidence: 99%

Stalled Polη at its cognate substrate initiates an alternative translesion synthesis pathway via interaction with REV1

Ito¹,

Yokoi²,

Sakayoshi³

et al. 2012

Genes to Cells

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“…It substantially distorts DNA and no single DNA polymerases in human cells can complete the translesion synthesis reaction alone. Both of the Y-family enzymes pol ι and pol η are involved in bypass and associated mutagenesis by UV radiation [26][27][28][29]. Pol ι is the only bypass DNA polymerase in human cells that correctly inserts an A opposite the first T of (6-4)PP; insertion opposite the second T of a (6-4)PP is errorprone [19].…”

Section: Mismatch Extension and Translesion Dna Synthesismentioning

confidence: 99%

DNA polymerase θ (POLQ) can extend from mismatches and from bases opposite a (6-4) photoproduct

Seki

Wood

2008

DNA Repair

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DNA polymerase θ (pol θ) is a nuclear A-family DNA polymerase encoded by the POLQ gene in vertebrate cells. The biochemical properties of pol θ and of Polq-defective mice have suggested that pol θ participates in DNA damage tolerance. For example, pol θ was previously found to be proficient not only in incorporation of a nucleotide opposite a thymine glycol or an abasic site, but also extends a polynucleotide chain efficiently from the base opposite the lesion. We carried out experiments to determine whether this ability to extend from non-standard termini is a more general property of the enzyme. Pol θ extended relatively efficiently from matched termini as well as termini with A:G, A:T, and A:C mismatches, with less descrimination than a well-studied A family DNA polymerase, exonuclease-free pol I from E. coli. Although pol θ was unable to, by itself, bypass a cyclobutane pyrimidine dimer or a (6-4) photoproduct, it could perform some extension from primers with bases placed across from these lesions. When pol θ was combined with DNA polymerase ι , an enzyme that can insert a base opposite a UV-induced (6-4) photoproduct, complete bypass of a (6-4) photoproduct was possible. These data show that in addition to its ability to insert nucleotides opposite some DNA lesions, pol θ is proficient at extension of unpaired termini. These results show the potential of pol θ to act as an extender after incorporation of nucleotides by other DNA polymerases, and aid in understanding the role of pol θ in somatic mutagenesis and genome instability.

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“…Furthermore, the results of our biological and biochemical experiments strongly suggest that REV1 recruits pol to a stalled replication site through the interaction with the REV7 subunit of pol , and this recruitment mechanism plays an important role for pol to catalyze TLS. (34). Their genotypes were confirmed by genomic PCR (supplemental Fig.…”

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confidence: 99%

The Vital Role of Polymerase ζ and REV1 in Mutagenic, but Not Correct, DNA Synthesis across Benzo[a]pyrene-dG and Recruitment of Polymerase ζ by REV1 to Replication-stalled Site

Hashimoto

Cho

Yang

et al. 2012

Journal of Biological Chemistry

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Background: dG lesion derived from potent carcinogen benzo[a]pyrene causes mutations through DNA replication. Results: Pol and REV1 are essential to mutagenic, but not accurate, translesion DNA synthesis. Conclusion: DNA synthesis across identical DNA damage can be catalyzed by a different set of polymerases. Significance: The results have revealed an important role for DNA polymerases, pol and REV1, in inducing mutations.

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UV-B Radiation Induces Epithelial Tumors in Mice Lacking DNA Polymerase η and Mesenchymal Tumors in Mice Deficient for DNA Polymerase ι

Cited by 106 publications

References 74 publications

Stalled Polη at its cognate substrate initiates an alternative translesion synthesis pathway via interaction with REV1

Stalled Polη at its cognate substrate initiates an alternative translesion synthesis pathway via interaction with REV1

DNA polymerase θ (POLQ) can extend from mismatches and from bases opposite a (6-4) photoproduct

The Vital Role of Polymerase ζ and REV1 in Mutagenic, but Not Correct, DNA Synthesis across Benzo[a]pyrene-dG and Recruitment of Polymerase ζ by REV1 to Replication-stalled Site

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