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.
Highlights
Apoptosis induced by DNA damage is an important mechanism of tumor suppression and it is significant in cancer chemotherapy
Damaged-DNA Binding Protein-2 (DDB2)-mediated proteolysis of p21 is a key activator of apoptosis following DNA damage Linn laboratory demonstrated that the DDB2 -/- MEFs as well as xeroderma pigmentosum group E (XP-E) cells are deficient in apoptosis following UV irradiation [30,31]
The E2F1-induced apoptosis was restored in the DDB2-/-p21-/- MEFs. Together those observations clearly demonstrated that the lack of proteolysis of p21 and consequent accumulation of p21 in the DDB2-deficient cells is responsible for the inhibition of apoptosis following DNA damage
Summary
Apoptosis induced by DNA damage is an important mechanism of tumor suppression and it is significant in cancer chemotherapy. For cells to undergo apoptosis after DNA damage, mechanisms must exist that reduce the level of p21 to support activation of the caspases. Recent studies by Stoyanova et al [15] demonstrated that DDB2 targets p21 for ubiquitination and proteolysis in cells harboring DNA damage.
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