Damaged-DNA Binding Protein-2 Drives Apoptosis Following DNA Damage
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Damaged-DNA Binding Protein-2 Drives Apoptosis Following DNA Damage Srilata Bagchi1, Pradip Raychaudhuri2*
Abstract Apoptosis induced by DNA damage is an important mechanism of tumor suppression and it is significant also in cancer chemotherapy. Mammalian cells activate the pathways of p53 to induce apoptosis of cells harboring irreparable DNA damages. While p53 induces expression of various pro-apoptotic genes and directly participates in the disruption of mitochondrial membrane polarization, it also increases expression of the cell cycle inhibitor p21 that is a dominant inhibitor of caspase-activation and apoptosis. Here we discuss how Damaged-DNA Binding Protein-2 (DDB2) subdues the level of p21 in cells harboring irreparable DNA damage to support activation of the caspases. We speculate a model in which DDB2 detects and couples the presence of un-repaired DNA damages to the proteolysis of p21, leading to the induction of apoptosis. Review Cell cycle inhibitor p21 inhibits apoptosis following DNA damage
The DNA damage response pathways are critical mechanisms of tumor suppression, as these pathways prevent accumulation of cells with oncogenic mutations. Often the DNA repair pathways are insufficient to repair all the damages. Under these circumstances permanent arrest (premature senescence) or apoptosis is induced to prevent accumulation of cells with oncogenic mutations. It is unclear how cells sense the presence of irreparable DNA damage - a situation when the extent of damage is greater than repair-capacity of a cell. It is expected that premature senescence or apoptosis would be induced only after the cell has a window of opportunity to repair the damages. A likely scenario is that a continued activation of the ATM/ATR beyond the attempts to repair the damages is responsible for the induction of premature senescence or apoptosis. Apoptosis is clearly the most effective tumor suppression mechanism following DNA damage because it eliminates the cells harboring irreparable DNA damages. The tumor suppressor p53 is considered to be the central activator of the DNA damage-induced apoptosis. Activated ATM/ATR cause stabilization and activation of p53 (Reviewed in [1]). * Correspondence: [email protected] 2 Department of Biochemistry and Molecular Genetics (M/C 669), Cancer Center, University of Illinois at Chicago, 900 S. Ashland Ave, Chicago, IL60607, USA
Once activated, p53 directly and indirectly causes disruption of mitochondrial membrane polarization, leading to the activation of caspases - Apoptosis ensues. Mechanisms of p53 involve transcriptional activation of pro-apoptotic genes and inhibition of anti-apoptotic genes. For example, p53 transcriptionally activates expression of PUMA, BID, BAX, and NOXA (Reviewed in [2]) to induce apoptosis. Also, the anti-apoptotic protein Survivin is inhibited by p53 [3]. In addition to these mechanisms, p53 also translocates to mitochondria and directly binds to Bcl-2 and inhibits its anti-apoptotic activity. This latter phenomenon is termed transcript
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