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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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Related in: MedlinePlus

Schematic diagram depicting how DDB2 can be targeted therapeutically for the treatment of cancer and aging. DDB2 expression is reduced during carcinoma progression. DDB2 up-regulation can be therapeutically achieved to induce senescence and apoptosis response to inhibit tumorigenesis. In contrast, DDB2 expression is augmented with aging. Hence, attenuation of DDB2 expression might prove to be beneficial to inhibit aging and age related disorders.
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f2-ijms-13-11012: Schematic diagram depicting how DDB2 can be targeted therapeutically for the treatment of cancer and aging. DDB2 expression is reduced during carcinoma progression. DDB2 up-regulation can be therapeutically achieved to induce senescence and apoptosis response to inhibit tumorigenesis. In contrast, DDB2 expression is augmented with aging. Hence, attenuation of DDB2 expression might prove to be beneficial to inhibit aging and age related disorders.

Mentions: Senescence is often regarded as a classic case of antagonistic pleiotropy [66]. Antagonistic pleiotropy is defined as the production of multiple contrasting phenotypic effects by a single biological process. Generally, some of the effects are beneficial to the organism, whereas the others are detrimental. Senescence is preferred by natural selection to promote fitness and survival advantage in young organisms (i.e., suppressing cancer) over its detrimental effect in aged organisms (i.e., age related pathophysiologies). In young individuals increased DDB2 expression is beneficial to prevent cancer by induction of senescence and apoptosis. However, at a later stage of life, high-level DDB2 might be detrimental because of increased ROS accumulation and ROS-associated abnormalities (Figure 2). Hence, regulation of DDB2 gene expression and, in turn, DDB2 mediated gene expression might vary in different contexts. Further, DDB2 expression is attenuated in a wide variety of cancers at the RNA level [67]. It has been validated at the protein level as well in basal cell carcinoma patient samples where there is evidence for loss of DDB2 expression compared to the normal tissue [51]. Hence, it is important to recognize how DDB2 expression is lost during carcinoma progression and will be important to determine whether restoration of DDB2 expression helps to prevent tumor development. On the other hand, it is also necessary to examine how DDB2 is stabilized during aging that leads to age related disorders. DDB2 is a p53-induced gene. Therefore, it is a possibility that DDB2 expression is attenuated with the loss of p53 function in cancer. Also, DDB2 transcription start site is TATA-less, G/C rich and consists of Sp1 and NF1 elements [23]. Housekeeping genes and cell cycle regulated genes are frequently associated with aforementioned elements. These observations clearly indicate that DDB2 is under tight gene expression control and there might be several other factors that regulate its expression. As DDB2 promoter is G/C rich, it will be important to examine whether there is an increased hypermethylation of the CpG islands in the promoter of DDB2 with the carcinoma progression. For several genes, such as p16INK4a, promoter hypermethylation mediated repression has been evidenced in cancer cells [68]. Restoration of DDB2 expression will induce ROS accumulation that would inhibit tumor progression through senescence or apoptosis. Can any pharmacological agent augment re-expression of DDB2? The ROS-mediated expression of DDB2 can be exploited to elevate DDB2 expression. There are several pharmacological agents that are currently being explored to promote ROS generation in cancer cells as a means to kill the cells. These drugs act on the transformed cells selectively as they exhibit elevated ROS generation associated with active metabolism and oncogenic stimulation. Some of these agents directly induce ROS generation such as Motexafin Gadolinium, which is a pro-oxidant catalyst and induces intracellular superoxide generation. Agents that inhibit elimination of ROS have been more successful in the treatment of patients. These drugs target different anti-oxidant pathways. Phenylethyl Isothiocyanate (PEITC) and Imexon cause depletion of GSH [69]. Also, the SOD inhibitors, such as 2-methoxyestradiol and Tetrathiomolybdate, and catalase inhibitors, such as Mangafodipir increase ROS. Many of these pharmacological agents are already in phase II/III clinical trial and proved to be effective in the treatment of certain types of cancer [69]. PEITC, a natural compound found in cruciferous vegetables, has been reported to be effective against wide variety of cancers [69,70]. PEITC has been reported to inhibit ovarian and prostate tumor progression [71]. It is presently in clinical trial for the treatment of lung cancer and lymphoproliferative disorders. Hence, being a natural compound with less toxicity, PEITC seems like an attractive agent for induction of DDB2 in cancer patients. PEITC induced DDB2 expression will keep the ROS level high by down regulation of anti-oxidant genes MnSOD and catalase and trigger apoptosis/senescence of transformed cells.


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 can be targeted therapeutically for the treatment of cancer and aging. DDB2 expression is reduced during carcinoma progression. DDB2 up-regulation can be therapeutically achieved to induce senescence and apoptosis response to inhibit tumorigenesis. In contrast, DDB2 expression is augmented with aging. Hence, attenuation of DDB2 expression might prove to be beneficial to inhibit aging and age related disorders.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2-ijms-13-11012: Schematic diagram depicting how DDB2 can be targeted therapeutically for the treatment of cancer and aging. DDB2 expression is reduced during carcinoma progression. DDB2 up-regulation can be therapeutically achieved to induce senescence and apoptosis response to inhibit tumorigenesis. In contrast, DDB2 expression is augmented with aging. Hence, attenuation of DDB2 expression might prove to be beneficial to inhibit aging and age related disorders.
Mentions: Senescence is often regarded as a classic case of antagonistic pleiotropy [66]. Antagonistic pleiotropy is defined as the production of multiple contrasting phenotypic effects by a single biological process. Generally, some of the effects are beneficial to the organism, whereas the others are detrimental. Senescence is preferred by natural selection to promote fitness and survival advantage in young organisms (i.e., suppressing cancer) over its detrimental effect in aged organisms (i.e., age related pathophysiologies). In young individuals increased DDB2 expression is beneficial to prevent cancer by induction of senescence and apoptosis. However, at a later stage of life, high-level DDB2 might be detrimental because of increased ROS accumulation and ROS-associated abnormalities (Figure 2). Hence, regulation of DDB2 gene expression and, in turn, DDB2 mediated gene expression might vary in different contexts. Further, DDB2 expression is attenuated in a wide variety of cancers at the RNA level [67]. It has been validated at the protein level as well in basal cell carcinoma patient samples where there is evidence for loss of DDB2 expression compared to the normal tissue [51]. Hence, it is important to recognize how DDB2 expression is lost during carcinoma progression and will be important to determine whether restoration of DDB2 expression helps to prevent tumor development. On the other hand, it is also necessary to examine how DDB2 is stabilized during aging that leads to age related disorders. DDB2 is a p53-induced gene. Therefore, it is a possibility that DDB2 expression is attenuated with the loss of p53 function in cancer. Also, DDB2 transcription start site is TATA-less, G/C rich and consists of Sp1 and NF1 elements [23]. Housekeeping genes and cell cycle regulated genes are frequently associated with aforementioned elements. These observations clearly indicate that DDB2 is under tight gene expression control and there might be several other factors that regulate its expression. As DDB2 promoter is G/C rich, it will be important to examine whether there is an increased hypermethylation of the CpG islands in the promoter of DDB2 with the carcinoma progression. For several genes, such as p16INK4a, promoter hypermethylation mediated repression has been evidenced in cancer cells [68]. Restoration of DDB2 expression will induce ROS accumulation that would inhibit tumor progression through senescence or apoptosis. Can any pharmacological agent augment re-expression of DDB2? The ROS-mediated expression of DDB2 can be exploited to elevate DDB2 expression. There are several pharmacological agents that are currently being explored to promote ROS generation in cancer cells as a means to kill the cells. These drugs act on the transformed cells selectively as they exhibit elevated ROS generation associated with active metabolism and oncogenic stimulation. Some of these agents directly induce ROS generation such as Motexafin Gadolinium, which is a pro-oxidant catalyst and induces intracellular superoxide generation. Agents that inhibit elimination of ROS have been more successful in the treatment of patients. These drugs target different anti-oxidant pathways. Phenylethyl Isothiocyanate (PEITC) and Imexon cause depletion of GSH [69]. Also, the SOD inhibitors, such as 2-methoxyestradiol and Tetrathiomolybdate, and catalase inhibitors, such as Mangafodipir increase ROS. Many of these pharmacological agents are already in phase II/III clinical trial and proved to be effective in the treatment of certain types of cancer [69]. PEITC, a natural compound found in cruciferous vegetables, has been reported to be effective against wide variety of cancers [69,70]. PEITC has been reported to inhibit ovarian and prostate tumor progression [71]. It is presently in clinical trial for the treatment of lung cancer and lymphoproliferative disorders. Hence, being a natural compound with less toxicity, PEITC seems like an attractive agent for induction of DDB2 in cancer patients. PEITC induced DDB2 expression will keep the ROS level high by down regulation of anti-oxidant genes MnSOD and catalase and trigger apoptosis/senescence of transformed cells.

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