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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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Regulation of MGMT transcription. (A) Regulation of MGMT promoter and MGMT-mediated repair of DNA alkylation damage. (B) Structure of the human MGMT promoter showing the positions of transcription factor-binding sites.
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gkt635-F2: Regulation of MGMT transcription. (A) Regulation of MGMT promoter and MGMT-mediated repair of DNA alkylation damage. (B) Structure of the human MGMT promoter showing the positions of transcription factor-binding sites.

Mentions: O6-methylguanine-DNA methyltransferase (MGMT), alias alkyltransferase, does not need cofactors or another ‘helper’ protein; it represents a one-step repair mechanism, which is responsible for the removal of alkyl groups from the O6-position of guanine and the O4-position of thymine [for recent review see (126)] (Figure 2A). The question of induction of MGMT is highly important. First, if MGMT upregulation occurred, it would protect against O6-alkylating environmental and tobacco smoke carcinogens (127). Second, it would have a high impact on cancer therapy, as tumours like glioblastoma and metastatic melanoma are treated with O6-alkylating agents (temozolomide, dacarbazine, chloroethylating nitrosoureas) against which MGMT offers protection. Notably, in glioma therapy, ionizing radiation is applied concomitantly with temozolomide (nearly daily for a period of 30 days, total 60 Gy). In addition, corticosteroids are administered to reduce oedema and inflammation. An upregulation of MGMT in tumour cells provoked either by temozolomide, ionizing radiation or corticosteroid treatment would render the therapy with O6-alkylating agents inefficient. Therefore, it is of upmost importance to understand how MGMT is regulated by genotoxic stress and also by non-genotoxic gene activators.Figure 2.


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 MGMT transcription. (A) Regulation of MGMT promoter and MGMT-mediated repair of DNA alkylation damage. (B) Structure of the human MGMT promoter showing the positions of transcription factor-binding sites.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

gkt635-F2: Regulation of MGMT transcription. (A) Regulation of MGMT promoter and MGMT-mediated repair of DNA alkylation damage. (B) Structure of the human MGMT promoter showing the positions of transcription factor-binding sites.
Mentions: O6-methylguanine-DNA methyltransferase (MGMT), alias alkyltransferase, does not need cofactors or another ‘helper’ protein; it represents a one-step repair mechanism, which is responsible for the removal of alkyl groups from the O6-position of guanine and the O4-position of thymine [for recent review see (126)] (Figure 2A). The question of induction of MGMT is highly important. First, if MGMT upregulation occurred, it would protect against O6-alkylating environmental and tobacco smoke carcinogens (127). Second, it would have a high impact on cancer therapy, as tumours like glioblastoma and metastatic melanoma are treated with O6-alkylating agents (temozolomide, dacarbazine, chloroethylating nitrosoureas) against which MGMT offers protection. Notably, in glioma therapy, ionizing radiation is applied concomitantly with temozolomide (nearly daily for a period of 30 days, total 60 Gy). In addition, corticosteroids are administered to reduce oedema and inflammation. An upregulation of MGMT in tumour cells provoked either by temozolomide, ionizing radiation or corticosteroid treatment would render the therapy with O6-alkylating agents inefficient. Therefore, it is of upmost importance to understand how MGMT is regulated by genotoxic stress and also by non-genotoxic gene activators.Figure 2.

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