DNA Polymerase ζ Accounts for the Reduced Cytotoxicity and Enhanced Mutagenicity of Cisplatin in Human Colon Carcinoma Cells That Have Lost DNA Mismatch Repair

Lin, Xi Zhang; Trang, Julie; Okuda, Tsuyoshi; Howell, Stephen B.

doi:10.1158/1078-0432.ccr-05-1380

Cited by 42 publications

(39 citation statements)

References 35 publications

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“…Recently therapeutic inhibition of Pol ζ has been proposed for the reduction of mutagenesis in cancer cells [36]. Our results suggest that such inhibition may adversely impact mtDNA.…”

Section: Discussionmentioning

confidence: 52%

Analysis of Rev1p and Pol ζ in mitochondrial mutagenesis suggests an alternative pathway of damage tolerance

Kalifa

Sia

2007

DNA Repair

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Ultraviolet light is a potent DNA damaging agent that induces bulky lesions in DNA which block the replicative polymerases. In order to ensure continued DNA replication and cell viability, specialized translesion polymerases bypass these lesions at the expense of introducing mutations in the nascent DNA strand. A recent study has shown that the N-terminal sequences of the nuclear translesion polymerases Rev1p and Pol ζ can direct GFP to the mitochondrial compartment of Saccharomyces cerevisiae. We have investigated the role of these polymerases in mitochondrial mutagenesis. Our analysis of mitochondrial DNA point mutations, microsatellite instability, and the spectra of mitochondrial mutations indicate that these translesion polymerases function in a less mutagenic pathway in the mitochondrial compartment than they do in the nucleus. Mitochondrial phenotypes resulting from the loss of Rev1p and Pol ζ suggest that although these polymerases are responsible for the majority of mitochondrial frameshift mutations, they do not greatly contribute to mitochondrial DNA point mutations. Analysis of spontaneous mitochondrial DNA point mutations suggests that Pol ζ may play a role in general mitochondrial DNA maintenance. In addition, we observe a 20-fold increase in UV-induced mitochondrial DNA point mutations in rev deficient strains. Our data provides evidence for an alternative damage tolerance pathway that is specific to the mitochondrial compartment.

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“…Recently therapeutic inhibition of Pol ζ has been proposed for the reduction of mutagenesis in cancer cells [36]. Our results suggest that such inhibition may adversely impact mtDNA.…”

Section: Discussionmentioning

confidence: 52%

Analysis of Rev1p and Pol ζ in mitochondrial mutagenesis suggests an alternative pathway of damage tolerance

Kalifa

Sia

2007

DNA Repair

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“…This was later shown to be due to REV3L expression and activity (50), although a direct link between the two phenomena was not described. Additionally, homozygous deletions of REV3L in mice resulted in embryonic lethality due to an inability to repair genetic lesions that occur during the developmental process (84).…”

Section: Discussionmentioning

confidence: 99%

Functional Analysis of p53 Binding under Differential Stresses

Krieg

Hammond

Giaccia

2006

Molecular and Cellular Biology

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Hypoxia and DNA damage stabilize the p53 protein, but the subsequent effect that each stress has on transcriptional regulation of known p53 target genes is variable. We have used chromatin immunoprecipitation followed by CpG island (CGI) microarray hybridization to identify promoters bound by p53 under both DNA-damaging and non-DNA-damaging conditions in HCT116 cells. Using gene-specific PCR analysis, we have verified an association with CGIs of the highest enrichment (>2.5-fold) (REV3L, XPMC2H, HNRPUL1, TOR1AIP1, glutathione peroxidase 1, and SCFD2), with CGIs of intermediate enrichment (>2.2-fold) (COX7A2L, SYVN1, and JAG2), and with CGIs of low enrichment (>2.0-fold) (MYC and PCNA). We found little difference in promoter binding when p53 is stabilized by these two distinctly different stresses. However, expression of these genes varies a great deal: while a few genes exhibit classical induction with adriamycin, the majority of the genes are unchanged or are mildly repressed by either hypoxia or adriamycin. Further analysis using p53 mutated in the core DNA binding domain revealed that the interaction of p53 with CGIs may be occurring through both sequence-dependent and -independent mechanisms. Taken together, these experiments describe the identification of novel p53 target genes and the subsequent discovery of distinctly different expression phenomena for p53 target genes under different stress scenarios.The tumor microenvironment is a major factor influencing tumor growth, metastatic potential, and response to chemotherapeutic drugs and radiation therapy (7). The hypoxia-inducible factor (HIF) family of transcription factors regulates the expression of key enzymes in anaerobic glycolysis and proangiogenic factors (i.e., vascular endothelial growth factor), aiding cells in adapting to a low-oxygen environment (15). Thus, a tumor adapts to hypoxia first by sustaining itself via anaerobic metabolism and then by stimulating angiogenesis to acquire more nutrients and oxygen. However, the resulting vasculature tends to have aberrant structures with irregular blood flow and leaky walls, paradoxically creating regions of transient hypoxia and reoxygenation (76). Reoxygenation after hypoxia causes DNA damage, exacerbating genomic instability (25). The porous structure of the tumor vasculature may also provide an escape route for metastasizing cells. Repeated cycles of hypoxia, vascular formation, and reoxygenation select for cells that are more likely to survive in a restrictive environment. The consequences of this process are cancer cells that are more aggressive, more likely to metastasize, and more likely to be resistant to radiation and chemotherapy. Intimately tied to this process is the selection for cells that have lost the expression of functional p53 (19).A variety of cellular stresses, including DNA damage, oncogenic transformation, and hypoxia, stabilize the p53 protein by activating a host of stress-inducible kinases that phosphorylate p53 and MDM2, resulting in increased levels of p53 (17). Stabilized ...

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“…Knockdown of REV1 in ovarian cancer cell line 2008 and of REV3L in the colorectal tumor cell line HCT116 using shRNA also was associated with more sensitivity to cisplatin as measured by clonogenic assays, compared to the parental lines. Similarly, these mRNA suppressed cells had diminished spontaneous and cisplatin-induced mutagenesis in the HPRT gene [62,63]. Further, overexpression of REV1 in ovarian tumor lines led to some resistance to cisplatin and increased mutagenic frequency compared to parental lines [64].…”

Section: Consequences Of Rev3l Rev1 and Rev7 Reduction In Human Cellmentioning

confidence: 91%

DNA polymerase zeta (pol ζ) in higher eukaryotes

et al. 2007

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Most current knowledge about DNA polymerase zeta (pol ζ) comes from studies of the enzyme in the budding yeast Saccharomyces cerevisiae, where pol ζ consists of a complex of the catalytic subunit Rev3 with Rev7, which associates with Rev1. Most spontaneous and induced mutagenesis in yeast is dependent on these gene products, and yeast pol ζ can mediate translesion DNA synthesis past some adducts in DNA templates. Study of the homologous gene products in higher eukaryotes is in a relatively early stage, but additional functions for the eukaryotic proteins are already apparent. Suppression of vertebrate REV3L function not only reduces induced point mutagenesis but also causes larger-scale genome instability by raising the frequency of spontaneous chromosome translocations. Disruption of Rev3L function is tolerated in Drosophila, Arabidopsis, and in vertebrate cell lines under some conditions, but is incompatible with mouse embryonic development. Functions for REV3L and REV7(MAD2B) in higher eukaryotes have been suggested not only in translesion DNA synthesis but also in some forms of homologous recombination, repair of interstrand DNA crosslinks, somatic hypermutation of immunoglobulin genes and cell-cycle control. This review discusses recent developments in these areas.

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DNA Polymerase ζ Accounts for the Reduced Cytotoxicity and Enhanced Mutagenicity of Cisplatin in Human Colon Carcinoma Cells That Have Lost DNA Mismatch Repair

Cited by 42 publications

References 35 publications

Analysis of Rev1p and Pol ζ in mitochondrial mutagenesis suggests an alternative pathway of damage tolerance

Analysis of Rev1p and Pol ζ in mitochondrial mutagenesis suggests an alternative pathway of damage tolerance

Functional Analysis of p53 Binding under Differential Stresses

DNA polymerase zeta (pol ζ) in higher eukaryotes

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