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DNA polymerase zeta is essential for hexavalent chromium-induced mutagenesis.

Publication ,  Journal Article
O'Brien, TJ; Witcher, P; Brooks, B; Patierno, SR
Published in: Mutat Res
April 26, 2009

Translesion synthesis (TLS) is a unique DNA damage tolerance mechanism involved in the replicative bypass of genetic lesions in favor of uninterrupted DNA replication. TLS is critical for the generation of mutations by many different chemical and physical agents, however, there is no information available regarding the role of TLS in carcinogenic metal-induced mutagenesis. Hexavalent chromium (Cr(VI))-containing compounds are highly complex genotoxins possessing both mutagenic and clastogenic activities. The focus of this work was to determine the impact that TLS has on Cr(VI)-induced mutagenesis in Saccharomyces cerevisiae. Wild-type yeast and strains deficient in TLS polymerases (i.e. Polzeta (rev3), Poleta (rad30)) were exposed to Cr(VI) and monitored for cell survival and forward mutagenesis at the CAN1 locus. In general, TLS deficiency had little impact on Cr(VI)-induced clonogenic lethality or cell growth. rad30 yeast exhibited higher levels of basal and induced mutagenesis compared to Wt and rev3 yeast. In contrast, rev3 yeast displayed attenuated Cr(VI)-induced mutagenesis. Moreover, deletion of REV3 in rad30 yeast (rad30 rev3) resulted in a significant decrease in basal and Cr(VI) mutagenesis relative to Wt and rad30 single mutants indicating that mutagenesis primarily depended upon Polzeta. Interestingly, rev3 yeast were similar to Wt yeast in susceptibility to Cr(VI)-induced frameshift mutations. Mutational analysis of the CAN1 gene revealed that Cr(VI)-induced base substitution mutations accounted for 83.9% and 100.0% of the total mutations in Wt and rev3 yeast, respectively. Insertions and deletions comprised 16.1% of the total mutations in Cr(VI) treated Wt yeast but were not observed rev3 yeast. This work provides novel information regarding the molecular mechanisms of Cr(VI)-induced mutagenesis and is the first report demonstrating a role for TLS in the fixation of mutations induced by a carcinogenic metal.

Duke Scholars

Published In

Mutat Res

DOI

ISSN

0027-5107

Publication Date

April 26, 2009

Volume

663

Issue

1-2

Start / End Page

77 / 83

Location

Netherlands

Related Subject Headings

  • Saccharomyces cerevisiae Proteins
  • Saccharomyces cerevisiae
  • Oncology & Carcinogenesis
  • Mutagenesis
  • Molecular Sequence Data
  • Microbial Viability
  • Frameshift Mutation
  • DNA-Directed DNA Polymerase
  • DNA Mutational Analysis
  • DNA Damage
 

Citation

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O’Brien, T. J., Witcher, P., Brooks, B., & Patierno, S. R. (2009). DNA polymerase zeta is essential for hexavalent chromium-induced mutagenesis. Mutat Res, 663(1–2), 77–83. https://doi.org/10.1016/j.mrfmmm.2009.01.012
O’Brien, Travis J., Preston Witcher, Bradford Brooks, and Steven R. Patierno. “DNA polymerase zeta is essential for hexavalent chromium-induced mutagenesis.Mutat Res 663, no. 1–2 (April 26, 2009): 77–83. https://doi.org/10.1016/j.mrfmmm.2009.01.012.
O’Brien TJ, Witcher P, Brooks B, Patierno SR. DNA polymerase zeta is essential for hexavalent chromium-induced mutagenesis. Mutat Res. 2009 Apr 26;663(1–2):77–83.
O’Brien, Travis J., et al. “DNA polymerase zeta is essential for hexavalent chromium-induced mutagenesis.Mutat Res, vol. 663, no. 1–2, Apr. 2009, pp. 77–83. Pubmed, doi:10.1016/j.mrfmmm.2009.01.012.
O’Brien TJ, Witcher P, Brooks B, Patierno SR. DNA polymerase zeta is essential for hexavalent chromium-induced mutagenesis. Mutat Res. 2009 Apr 26;663(1–2):77–83.
Journal cover image

Published In

Mutat Res

DOI

ISSN

0027-5107

Publication Date

April 26, 2009

Volume

663

Issue

1-2

Start / End Page

77 / 83

Location

Netherlands

Related Subject Headings

  • Saccharomyces cerevisiae Proteins
  • Saccharomyces cerevisiae
  • Oncology & Carcinogenesis
  • Mutagenesis
  • Molecular Sequence Data
  • Microbial Viability
  • Frameshift Mutation
  • DNA-Directed DNA Polymerase
  • DNA Mutational Analysis
  • DNA Damage