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Review
. 2013 Oct;41(18):8403-20.
doi: 10.1093/nar/gkt635. Epub 2013 Jul 27.

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

Markus Christmann  1 , Bernd Kaina
Affiliations
Review

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

Markus Christmann et al. Nucleic Acids Res. 2013 Oct.

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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Figures

Figure 1.
Figure 1.
Transcription factors and signalling involved in repair gene regulation. (A) Transcription factors involved in genotoxin-triggered transcriptional activation of DNA repair genes. (B) Growth factor and DDR triggered activation of transcription factors involved in repair gene regulation.
Figure 2.
Figure 2.
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.
Figure 3.
Figure 3.
Regulation of BER genes. (A) Mechanism of BER. (B) BER genes and transcription factors that were reported to be regulated by genotoxic stress.
Figure 4.
Figure 4.
Regulation of NER. (A) Mechanism of NER and key proteins involved. (B) NER genes and transcription factors regulated by genotoxic stress.
Figure 5.
Figure 5.
Genotoxin-triggered transcriptional repair gene regulation. (A) Pathways of upregulation of DDB2, XPC and XPF. (B) Different modes of repair gene regulation; for explanation, see text.
See this image and copyright information in PMC

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