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Transcriptional regulation of human DNA repair genes following genotoxic stress: trigger mechanisms, inducible responses and genotoxic adaptation.

Christmann M, Kaina B - Nucleic Acids Res. (2013)

Bottom Line: Therefore, their balanced expression is important for avoiding erroneous repair that might result from excessive base removal and DNA cleavage.Here, we review transcriptional regulation of DNA repair genes in normal and cancer cells and describe mechanisms of promoter activation following genotoxic exposures through environmental carcinogens and anticancer drugs.The data available to date indicate that 25 DNA repair genes are subject to regulation following genotoxic stress in rodent and human cells, but for only a few of them, the data are solid as to the mechanism, homeostatic regulation and involvement in an adaptive response to genotoxic stress.

View Article: PubMed Central - PubMed

Affiliation: Department of Toxicology, University Medical Center, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany.

ABSTRACT
DNA repair is the first barrier in the defense against genotoxic stress. In recent years, mechanisms that recognize DNA damage and activate DNA repair functions through transcriptional upregulation and post-translational modification were the focus of intensive research. Most DNA repair pathways are complex, involving many proteins working in discrete consecutive steps. Therefore, their balanced expression is important for avoiding erroneous repair that might result from excessive base removal and DNA cleavage. Amelioration of DNA repair requires both a fine-tuned system of lesion recognition and transcription factors that regulate repair genes in a balanced way. Transcriptional upregulation of DNA repair genes by genotoxic stress is counteracted by DNA damage that blocks transcription. Therefore, induction of DNA repair resulting in an adaptive response is only visible through a narrow window of dose. Here, we review transcriptional regulation of DNA repair genes in normal and cancer cells and describe mechanisms of promoter activation following genotoxic exposures through environmental carcinogens and anticancer drugs. The data available to date indicate that 25 DNA repair genes are subject to regulation following genotoxic stress in rodent and human cells, but for only a few of them, the data are solid as to the mechanism, homeostatic regulation and involvement in an adaptive response to genotoxic stress.

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Related in: MedlinePlus

Regulation of BER genes. (A) Mechanism of BER. (B) BER genes and transcription factors that were reported to be regulated by genotoxic stress.
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gkt635-F3: Regulation of BER genes. (A) Mechanism of BER. (B) BER genes and transcription factors that were reported to be regulated by genotoxic stress.

Mentions: BER removes single bases damaged by oxidation, methylation and other small chemical modifications from DNA. The first step in BER is executed by glycosylases, such as 8-oxoguanine-DNA glycosylase (OGG1), 3-methyladenine-DNA glycosylase (MPG) or endonuclease VIII-like 1 (NEIL1), which remove modified purines and pyrimidines from DNA leaving apurinic/apyrimidinic sites. These sites are converted into DNA single-strand breaks, which is catalysed by the apurinic/apyrimidinic endonuclease (APE1, APEX, REF-1). During short patch BER, the remaining sugar backbone is removed by DNA polymerase β, which also inserts a new nucleotide. During long-patch BER, the flap endonuclease 1 (FEN1) stimulates strand displacement and repair synthesis via DNA polymerase β. The X-ray repair cross-complementing protein-1 (XRCC1), which interacts with DNA ligase III and polymerase β, is involved in the ligation step during short-patch BER, and the DNA ligase I (LIG1) performs the ligation step during long-patch BER (Figure 3A). The following BER genes have been described to be subject to transcriptional upregulation.Figure 3.


Transcriptional regulation of human DNA repair genes following genotoxic stress: trigger mechanisms, inducible responses and genotoxic adaptation.

Christmann M, Kaina B - Nucleic Acids Res. (2013)

Regulation of BER genes. (A) Mechanism of BER. (B) BER genes and transcription factors that were reported to be regulated by genotoxic stress.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3794595&req=5

gkt635-F3: Regulation of BER genes. (A) Mechanism of BER. (B) BER genes and transcription factors that were reported to be regulated by genotoxic stress.
Mentions: BER removes single bases damaged by oxidation, methylation and other small chemical modifications from DNA. The first step in BER is executed by glycosylases, such as 8-oxoguanine-DNA glycosylase (OGG1), 3-methyladenine-DNA glycosylase (MPG) or endonuclease VIII-like 1 (NEIL1), which remove modified purines and pyrimidines from DNA leaving apurinic/apyrimidinic sites. These sites are converted into DNA single-strand breaks, which is catalysed by the apurinic/apyrimidinic endonuclease (APE1, APEX, REF-1). During short patch BER, the remaining sugar backbone is removed by DNA polymerase β, which also inserts a new nucleotide. During long-patch BER, the flap endonuclease 1 (FEN1) stimulates strand displacement and repair synthesis via DNA polymerase β. The X-ray repair cross-complementing protein-1 (XRCC1), which interacts with DNA ligase III and polymerase β, is involved in the ligation step during short-patch BER, and the DNA ligase I (LIG1) performs the ligation step during long-patch BER (Figure 3A). The following BER genes have been described to be subject to transcriptional upregulation.Figure 3.

Bottom Line: Therefore, their balanced expression is important for avoiding erroneous repair that might result from excessive base removal and DNA cleavage.Here, we review transcriptional regulation of DNA repair genes in normal and cancer cells and describe mechanisms of promoter activation following genotoxic exposures through environmental carcinogens and anticancer drugs.The data available to date indicate that 25 DNA repair genes are subject to regulation following genotoxic stress in rodent and human cells, but for only a few of them, the data are solid as to the mechanism, homeostatic regulation and involvement in an adaptive response to genotoxic stress.

View Article: PubMed Central - PubMed

Affiliation: Department of Toxicology, University Medical Center, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany.

ABSTRACT
DNA repair is the first barrier in the defense against genotoxic stress. In recent years, mechanisms that recognize DNA damage and activate DNA repair functions through transcriptional upregulation and post-translational modification were the focus of intensive research. Most DNA repair pathways are complex, involving many proteins working in discrete consecutive steps. Therefore, their balanced expression is important for avoiding erroneous repair that might result from excessive base removal and DNA cleavage. Amelioration of DNA repair requires both a fine-tuned system of lesion recognition and transcription factors that regulate repair genes in a balanced way. Transcriptional upregulation of DNA repair genes by genotoxic stress is counteracted by DNA damage that blocks transcription. Therefore, induction of DNA repair resulting in an adaptive response is only visible through a narrow window of dose. Here, we review transcriptional regulation of DNA repair genes in normal and cancer cells and describe mechanisms of promoter activation following genotoxic exposures through environmental carcinogens and anticancer drugs. The data available to date indicate that 25 DNA repair genes are subject to regulation following genotoxic stress in rodent and human cells, but for only a few of them, the data are solid as to the mechanism, homeostatic regulation and involvement in an adaptive response to genotoxic stress.

Show MeSH
Related in: MedlinePlus