Limits...
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.

Show MeSH

Related in: MedlinePlus

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.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3794595&req=5

gkt635-F5: 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.

Mentions: It should also be recalled that genotoxins induce a broad spectrum of lesions, many of which block transcription. Therefore, an adverse side effect of genotoxin exposure is downregulation of DNA repair itself. To counteract genotoxin-triggered transcriptional inhibition, cells are equipped with maintenance functions. An example is provided by UV light and bulky DNA damage-generating agents that induce c-Fos as immediate-early and late response (71) following treatment. This induction of c-Fos/AP-1 is important for cell cycle and repair regulation following DNA damage, as shown in experiments with c-Fos-lacking cells. c-fos knockout and knockdown cells are hypersensitive to UV light and chemical genotoxins. Cells show a higher than normal DNA adduct level and enhanced replication and transcription blockage (70,175,176). Repair of DNA adducts is slow in c-Fos-lacking cells because of a decline in short-lived mRNAs of genes encoding NER proteins, notably XPF and XPG (Figure 5A). These mRNAs are declining due to the UV-induced block to transcription. In normal cells, c-Fos is induced immediately after UV irradiation, which triggers xpf and xpg resynthesis and stimulates NER (70,71). Therefore, the genotoxin-triggered c-Fos response counteracts genotoxin-induced downregulation of these NER genes (Figure 5A). Of note, XPF and XPG triggered by c-Fos/AP-1 are only slightly upregulated above the basal level after UV treatment (∼2-fold). Nevertheless, the stimulation of the xpf and xpg promoter following genotoxic stress is important, as it maintains the NER capacity of the cell following genotoxic stress, resulting in better removal of CPD lesions and survival. This type of induction might be designated as homeostatic or maintenance regulation (Figure 5B). It might be generally important for repair proteins whose expression above a critical level is deleterious, which seems to be the case for endonucleases like XPF and XPG, and DNA glycosylases like MPG (177).Figure 5.


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)

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.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

gkt635-F5: 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.
Mentions: It should also be recalled that genotoxins induce a broad spectrum of lesions, many of which block transcription. Therefore, an adverse side effect of genotoxin exposure is downregulation of DNA repair itself. To counteract genotoxin-triggered transcriptional inhibition, cells are equipped with maintenance functions. An example is provided by UV light and bulky DNA damage-generating agents that induce c-Fos as immediate-early and late response (71) following treatment. This induction of c-Fos/AP-1 is important for cell cycle and repair regulation following DNA damage, as shown in experiments with c-Fos-lacking cells. c-fos knockout and knockdown cells are hypersensitive to UV light and chemical genotoxins. Cells show a higher than normal DNA adduct level and enhanced replication and transcription blockage (70,175,176). Repair of DNA adducts is slow in c-Fos-lacking cells because of a decline in short-lived mRNAs of genes encoding NER proteins, notably XPF and XPG (Figure 5A). These mRNAs are declining due to the UV-induced block to transcription. In normal cells, c-Fos is induced immediately after UV irradiation, which triggers xpf and xpg resynthesis and stimulates NER (70,71). Therefore, the genotoxin-triggered c-Fos response counteracts genotoxin-induced downregulation of these NER genes (Figure 5A). Of note, XPF and XPG triggered by c-Fos/AP-1 are only slightly upregulated above the basal level after UV treatment (∼2-fold). Nevertheless, the stimulation of the xpf and xpg promoter following genotoxic stress is important, as it maintains the NER capacity of the cell following genotoxic stress, resulting in better removal of CPD lesions and survival. This type of induction might be designated as homeostatic or maintenance regulation (Figure 5B). It might be generally important for repair proteins whose expression above a critical level is deleterious, which seems to be the case for endonucleases like XPF and XPG, and DNA glycosylases like MPG (177).Figure 5.

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