Investigation of the proapoptotic BCL-2 family member bid on the crossroad of the DNA damage response and apoptosis.
The BCL-2 family of apoptotic proteins encompasses key regulators proximal to irreversible cell damage. BID, a "BH3-only" proapoptotic family member, plays a critical role in connecting death signals through surface death receptors such as Fas and tumor necrosis factor-alpha to the core apoptotic pathway at the mitochondria. BID is activated downstream of death receptors by caspase-8 cleavage and N-myristoylation to target mitochondria where it activates BAX, BAK, and the downstream apoptotic pathway. In addition to its role in apoptosis, a role has been uncovered for BID in regulating the DNA damage-induced intra-S phase checkpoint that does not require its death-promoting BH3 domain. Following DNA damage, BID is found in the nucleus where it is phosphorylated by ATM and plays a role in the intra-S phase checkpoint. This checkpoint role is dependent on ATM-mediated phosphorylation at position 78. Thus, BID has two distinct and separable functions: an apoptotic function mediated by caspase cleavage and its BH3 domain and a cell cycle/DNA repair function mediated by phosphorylation by the DNA damage kinase ATM. Studies indicate that the pro-death activity of BID is inhibited by phosphorylation. Taken together, these findings suggest interaction between the two functions of BID. An area of intense research pursuit is determining what dictates how cells respond to DNA damage. Some cells arrest the cell cycle, whereas others undergo apoptosis. We hypothesize that BID acts at the interface between the DNA damage response and apoptosis, in position to signal a cell either to undergo cell cycle arrest and initiate DNA repair or to undergo apoptosis. This chapter describes the techniques used to characterize the role of BID in apoptosis and the DNA damage response.
Zinkel
Sandra S
SS
Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics / Q000502:physiology; D005455:Fluorescent Antibody Technique; D051379:Mice
D051023:BH3 Interacting Domain Death Agonist Protein