The Y-Family of DNA Polymerases

Ohmori, Hitoshi; Friedberg, Errol C.; Fuchs, Robert P. P.; Goodman, Myron F.; Hanaoka, Fumio; Hinkle, David C.; Kunkel, Thomas A.; Lawrence, Christopher W.; Livneh, Zvi; Nohmi, Takehiko; Prakash, Louise; Prakash, Satya; Todo, Tomoki; Walker, Graham C.; Wang, Zhigang; Woodgate, Roger

doi:10.1016/s1097-2765(01)00278-7

Cited by 804 publications

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“…The microarray data indicate that dinB ϩ transcript levels were increased in asynchronous WT cells after exposure to IR and this up-regulation of dinB ϩ in WT cells was confirmed using QPCR (see our Website). rev1 ϩ , like dinB ϩ , is a member of the Y-family of polymerases that are involved in error-prone translesion synthesis repair (Ohmori et al, 2001). Microarray data was not obtained for rev1 ϩ expression.…”

Section: Confirmation and Extension Of Array Data By Using Qpcrmentioning

confidence: 99%

Global Gene Expression Responses of Fission Yeast to Ionizing Radiation

Watson

Mata

Bähler

et al. 2004

MBoC

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A coordinated transcriptional response to DNA-damaging agents is required to maintain genome stability. We have examined the global gene expression responses of the fission yeast Schizosaccharomyces pombe to ionizing radiation (IR) by using DNA microarrays. We identified ϳ200 genes whose transcript levels were significantly altered at least twofold in response to 500 Gy of gamma IR in a temporally defined manner. The majority of induced genes were core environmental stress response genes, whereas the remaining genes define a transcriptional response to DNA damage in fission yeast. Surprisingly, few DNA repair and checkpoint genes were transcriptionally modulated in response to IR. We define a role for the stress-activated mitogen-activated protein kinase Sty1/Spc1 and the DNA damage checkpoint kinase Rad3 in regulating core environmental stress response genes and IR-specific response genes, both independently and in concert. These findings suggest a complex network of regulatory pathways coordinate gene expression responses to IR in eukaryotes. INTRODUCTIONExposure of cells to DNA-damaging agents such as ionizing radiation (IR) poses a significant threat to genome stability. Cells have therefore evolved complex response mechanisms to maintain genetic integrity after DNA damage. These include cell cycle delay, repair of DNA damage, transcriptional responses, and programmed cell death. Because disruption of any one of these DNA damage responses can lead to genomic instability and cancer, a comprehensive understanding of the individual components and their regulation is crucial.It is well established that many physiological responses to DNA damage are regulated at the level of gene expression. In Escherichia coli, the SOS response induces the expression of a network of genes after DNA damage through the regulatory LexA and RecA proteins (Friedberg et al., 1995). In lower eukaryotes, studies with the budding yeast Saccharomyces cerevisiae have identified a large number of damageinduced genes, including many involved in DNA metabolism and DNA repair (Aboussekhra et al., 1996;Gasch et al., 2001). In the distantly related fission yeast Schizosaccharomyces pombe, rhp51 ϩ , uvi15 ϩ , uvi31 ϩ , UVDE ϩ , and rhp16 ϩ have been shown to be DNA damage inducible (Bang et al., 1996;Davey et al., 1997;Shim et al., 2000).DNA damage checkpoint pathways function to delay the eukaryotic cell cycle in response to DNA damage, thus providing an opportunity for DNA repair. Central to the DNA damage checkpoint pathway are two highly conserved phosphoinositol-related kinases, Ataxia telangiectasia mutated (ATM) and ATM and Rad3-related (ATR) and their yeast homologs SpTel1 and SpRad3 in S. pombe, and ScTel1 and ScMec1 in S. cerevisiae. Activation of ATM and ATR kinases by DNA damage leads to cell cycle arrest through a number of downstream effector molecules including the effector kinases CHK1/SpChk1/ScChk1 and CHK2/SpCds1/ ScRad53 (for review, see Nyberg et al., 2002). In addition to regulating the cell cycle, DNA damage checkpoints also...

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Section: Confirmation and Extension Of Array Data By Using Qpcrmentioning

confidence: 99%

Global Gene Expression Responses of Fission Yeast to Ionizing Radiation

Watson

Mata

Bähler

et al. 2004

MBoC

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“…During last few years, a new class of DNA polymerases, the Y family, has been identified from both prokaryotic and eukaryotic sources [22][23][24][25]. In vitro, these enzymes are known to have the ability to bypass DNA lesions and also to have low processivity and extraordinarily low fidelity when replicating normal DNA.…”

Section: -Bis(2-chloroethyl)-1-nitrosourea (Bcnu) Is An Effectivementioning

confidence: 99%

Miscoding properties of 1,N6-ethanoadenine, a DNA adduct derived from reaction with the antitumor agent 1,3-bis(2-chloroethyl)-1-nitrosourea

Hang

Chenna

Guliaev

et al. 2003

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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“…The key components in TLS are low fidelity DNA polymerases that specialize in lesion bypass (9 -12). These proteins were conserved in evolution and are present in organisms ranging from Escherichia coli to humans (13). Humans contain at least four specialized DNA polymerases belonging to the Y superfamily (pol , pol , pol , and REV1) as well as several from other polymerase families (e.g.…”

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confidence: 99%

Quantitative Analysis of Translesion DNA Synthesis across a Benzo[a]pyrene-Guanine Adduct in Mammalian Cells

Avkin

Goldsmith

Velasco-Miguel

et al. 2004

Journal of Biological Chemistry

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177

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Replication across unrepaired DNA lesions in mammalian cells is effected primarily by specialized, low fidelity DNA polymerases. We studied translesion DNA synthesis (TLS) across a benzo[a]pyrene-guanine (BP-G) adduct, a major mutagenic DNA lesion generated by tobacco smoke. This was done using a quantitative assay that measures TLS indirectly, by measuring the recovery of gapped plasmids transfected into cultured mammalian cells. Analysis of PolK ؉/؉ mouse embryo fibroblasts (MEFs) showed that TLS across the BP-G adduct occurred with an efficiency of 48 ؎ 4%, which is an order of magnitude higher than in Escherichia coli. In PolK ؊/؊ MEFs, bypass was 16 ؎ 1%, suggesting that at least twothirds of the BP-G adducts in MEFs were bypassed exclusively by polymerase (pol ). In contrast, pol was not required for bypass across BP-G in a human XP-V cell line. Analysis of misinsertion specificity across BP-G revealed that bypass was more error-prone in MEFs lacking pol . Expression of pol from a plasmid introduced into PolK ؊/؊ MEFs restored both the extent and fidelity of bypass across BP-G. Pol was not required for bypass of a synthetic abasic site. In vitro analysis demonstrated efficient bypass across BP-G by both pol and pol , suggesting that the biological role of pol in TLS across BP-G is due to regulation of TLS and not due to an exclusive ability to bypass this lesion. These results indicate that BP-G is bypassed in mammalian cells with relatively high efficiency and that pol bypasses BP-G in vivo with higher efficiency and higher accuracy than other DNA polymerases.Genomic DNA is constantly subject to damage caused by both external agents, such as sunlight, and endogenous chemicals, such as reactive oxygen species. Most of this damage is eliminated by error-free DNA repair mechanisms, thereby restoring the DNA to its native sequence (1). However, a significant number of lesions escape repair and might therefore interfere with DNA replication and gene expression. Such interference can be mitigated by DNA damage tolerance mechanisms, primarily translesion DNA synthesis (TLS 1 ; also termed translesion replication) (2-5) and postreplicative recombinational repair (1, 6 -8). The key components in TLS are low fidelity DNA polymerases that specialize in lesion bypass (9 -12). These proteins were conserved in evolution and are present in organisms ranging from Escherichia coli to humans (13). Humans contain at least four specialized DNA polymerases belonging to the Y superfamily (pol , pol , pol , and REV1) as well as several from other polymerase families (e.g. pol (14), pol (15, 16), and pol (16, 17)). Many of these polymerases have been implicated in TLS in vitro (18 -24). However, there is a paucity of information about the efficiency and fidelity with which they support lesion bypass in living cells.Pol has a well established biological role in TLS, since it is mutated in all patients examined with the variant form of the hereditary disease xeroderma pigmentosum (10,18). This disease is characterized by sensitivi...

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The Y-Family of DNA Polymerases

Cited by 804 publications

References 3 publications

Global Gene Expression Responses of Fission Yeast to Ionizing Radiation

Global Gene Expression Responses of Fission Yeast to Ionizing Radiation

Miscoding properties of 1,N6-ethanoadenine, a DNA adduct derived from reaction with the antitumor agent 1,3-bis(2-chloroethyl)-1-nitrosourea

Quantitative Analysis of Translesion DNA Synthesis across a Benzo[a]pyrene-Guanine Adduct in Mammalian Cells

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