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Damaged DNA binding protein 2 in reactive oxygen species (ROS) regulation and premature senescence.

Roy N, Bagchi S, Raychaudhuri P - Int J Mol Sci (2012)

Bottom Line: Premature senescence induced by DNA damage or oncogene is a critical mechanism of tumor suppression.Here, we discuss how Damaged DNA binding Protein-2 (DDB2), a nucleotide excision repair protein, plays an important role in ROS regulation by epigenetically repressing the antioxidant genes MnSOD and Catalase.We further revisit a model in which DDB2 plays an instrumental role in DNA damage induced ROS accumulation, ROS induced premature senescence and inhibition of skin tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Genetics (M/C 669), University of Illinois at Chicago, 900 S. Ashland Ave, Chicago, IL 60607, USA; E-Mail: nroy4@uic.edu.

ABSTRACT
Premature senescence induced by DNA damage or oncogene is a critical mechanism of tumor suppression. Reactive oxygen species (ROS) have been implicated in the induction of premature senescence response. Several pathological disorders such as cancer, aging and age related neurological abnormalities have been linked to ROS deregulation. Here, we discuss how Damaged DNA binding Protein-2 (DDB2), a nucleotide excision repair protein, plays an important role in ROS regulation by epigenetically repressing the antioxidant genes MnSOD and Catalase. We further revisit a model in which DDB2 plays an instrumental role in DNA damage induced ROS accumulation, ROS induced premature senescence and inhibition of skin tumorigenesis.

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Schematic diagram depicting how DDB2 acts as a tumor suppressor by regulation of nucleotide excision repair, apoptosis and senescence.
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f1-ijms-13-11012: Schematic diagram depicting how DDB2 acts as a tumor suppressor by regulation of nucleotide excision repair, apoptosis and senescence.

Mentions: The tumor suppression function of DDB2 has been attributed to its in NER and apoptosis pathway [45]. However, recent studies from our group suggests that DDB2 mediated premature senescence response also serves an important part in its role as an inhibitor of UV induced skin carcinoma formation. DDB2−/− mice are deficient in apoptosis as well as repair of UV induced lesions following UV irradiation. In vitro studies suggested that accumulation of p21 Waf1/Cip1 in DDB2 deficiency causes this apoptosis and repair deficiency. Concordantly, DDB2−/− p21−/− mice exhibit efficient repair and apoptosis response following UV irradiation [51]. Surprisingly, in spite of efficient apoptosis and DNA repair function, DDB2−/− p21−/− develop skin tumor more aggressively than either WT or DDB2−/− mice [51]. Further investigation revealed that there was an acute deficiency in premature senescence response in DDB2−/− p21−/− mice following UV irradiation. The deficiency is associated with decrease in ROS accumulation in the skin of these mice. Also, there is increased catalase expression in the skin of the mice explaining the deficiency in ROS accumulation. DDB2−/− p21−/− mice also exhibited higher accumulation of transcriptional activator FoxM1, expression of which is inhibited by p21 Waf1/Cip1 [61]. Therefore, quite intriguingly, in the context of UV induced skin carcinoma progression, DDB2 and p21 Waf1/Cip1 cooperate with each other to inhibit tumorigenesis by induction of premature senescence. Therefore, the senescence induction by maintaining high ROS level is an important pathway through which DDB2 acts as a tumor suppressor (Figure1).


Damaged DNA binding protein 2 in reactive oxygen species (ROS) regulation and premature senescence.

Roy N, Bagchi S, Raychaudhuri P - Int J Mol Sci (2012)

Schematic diagram depicting how DDB2 acts as a tumor suppressor by regulation of nucleotide excision repair, apoptosis and senescence.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3472727&req=5

f1-ijms-13-11012: Schematic diagram depicting how DDB2 acts as a tumor suppressor by regulation of nucleotide excision repair, apoptosis and senescence.
Mentions: The tumor suppression function of DDB2 has been attributed to its in NER and apoptosis pathway [45]. However, recent studies from our group suggests that DDB2 mediated premature senescence response also serves an important part in its role as an inhibitor of UV induced skin carcinoma formation. DDB2−/− mice are deficient in apoptosis as well as repair of UV induced lesions following UV irradiation. In vitro studies suggested that accumulation of p21 Waf1/Cip1 in DDB2 deficiency causes this apoptosis and repair deficiency. Concordantly, DDB2−/− p21−/− mice exhibit efficient repair and apoptosis response following UV irradiation [51]. Surprisingly, in spite of efficient apoptosis and DNA repair function, DDB2−/− p21−/− develop skin tumor more aggressively than either WT or DDB2−/− mice [51]. Further investigation revealed that there was an acute deficiency in premature senescence response in DDB2−/− p21−/− mice following UV irradiation. The deficiency is associated with decrease in ROS accumulation in the skin of these mice. Also, there is increased catalase expression in the skin of the mice explaining the deficiency in ROS accumulation. DDB2−/− p21−/− mice also exhibited higher accumulation of transcriptional activator FoxM1, expression of which is inhibited by p21 Waf1/Cip1 [61]. Therefore, quite intriguingly, in the context of UV induced skin carcinoma progression, DDB2 and p21 Waf1/Cip1 cooperate with each other to inhibit tumorigenesis by induction of premature senescence. Therefore, the senescence induction by maintaining high ROS level is an important pathway through which DDB2 acts as a tumor suppressor (Figure1).

Bottom Line: Premature senescence induced by DNA damage or oncogene is a critical mechanism of tumor suppression.Here, we discuss how Damaged DNA binding Protein-2 (DDB2), a nucleotide excision repair protein, plays an important role in ROS regulation by epigenetically repressing the antioxidant genes MnSOD and Catalase.We further revisit a model in which DDB2 plays an instrumental role in DNA damage induced ROS accumulation, ROS induced premature senescence and inhibition of skin tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Genetics (M/C 669), University of Illinois at Chicago, 900 S. Ashland Ave, Chicago, IL 60607, USA; E-Mail: nroy4@uic.edu.

ABSTRACT
Premature senescence induced by DNA damage or oncogene is a critical mechanism of tumor suppression. Reactive oxygen species (ROS) have been implicated in the induction of premature senescence response. Several pathological disorders such as cancer, aging and age related neurological abnormalities have been linked to ROS deregulation. Here, we discuss how Damaged DNA binding Protein-2 (DDB2), a nucleotide excision repair protein, plays an important role in ROS regulation by epigenetically repressing the antioxidant genes MnSOD and Catalase. We further revisit a model in which DDB2 plays an instrumental role in DNA damage induced ROS accumulation, ROS induced premature senescence and inhibition of skin tumorigenesis.

Show MeSH
Related in: MedlinePlus