Proapoptotic BID Is an ATM Effector in the DNA-Damage Response

Abstract

The "BH3-only" proapoptotic BCL-2 family members are sentinels of intracellular damage. Here, we demonstrated that the BH3-only BID protein partially localizes to the nucleus in healthy cells, is important for apoptosis induced by DNA damage, and is phosphorylated following induction of double-strand breaks in DNA. We also found that BID phosphorylation is mediated by the ATM kinase and occurs in mouse BID on two ATM consensus sites. Interestingly, BID-/- cells failed to accumulate in the S phase of the cell cycle following treatment with the topoisomerase II poison etoposide; reintroducing wild-type BID restored accumulation. In contrast, introducing a nonphosphorylatable BID mutant did not restore accumulation in the S phase and resulted in an increase in cellular sensitivity to etoposide-induced apoptosis. These results implicate BID as an ATM effector and raise the possibility that proapoptotic BID may also play a prosurvival role important for S phase arrest.

BCL2 family in DNA damage and cell cycle control

“…62 These abnormal chromosomal structures represent 'chromatid-type' errors, resulting from improperly repaired DNA damage accrued during S phase of the cell 62 Bid À/À myeloid progenitor cells and MEFs fail to properly execute the ionizing radiation-induced intra-S-phase checkpoint. 62,63 This Sphase role is mediated through BID phosphorylation at position 78 by the DNA damage kinase ATM, demonstrating a direct link between BID and the DNA damage response. These studies demonstrate that BID plays a novel role in preserving genomic integrity that places BID at an early point in the path to determine the fate of a cell (Figure 2).…”

“…Casein kinases have been implicated in BID phosphorylation, and ATM has been shown to phosphorylate BID following DNA damage. [61][62][63] Phosphorylated BID is resistant to caspase cleavage in in vitro assays, and MEFs harboring phosphorylation-defective S78A BID are more sensitive to etoposide-induced cell death. The above data are consistent with a role for phosphorylation to inhibit activation of BID's proapoptotic function.…”

“…The above data are consistent with a role for phosphorylation to inhibit activation of BID's proapoptotic function. 61,63 How might BID be involved in suppressing leukemogenesis? Although the loss of BID could theoretically reset death susceptibility in both intrinsic and extrinsic pathways, it is less obvious why the absence of BID should prove so oncogenic.…”

BCL-2 in the crosshairs: tipping the balance of life and death

“…57 In addition to these internal familybased interactions, BCL-2 proteins associate with a host of other cellular proteins 31,47,[63][64][65][66][67][68][69][70][71] and have emerging roles in diverse physiologic pathways including glucose metabolism 20 and the DNA-damage response. 24,40 …”

The ATM–BID pathway plays a critical role in the DNA damage response by regulating mitochondria metabolism

“…1 Previously we have reported that DNA damage induces the phosphorylation of BID on serines 61 and 78 by the ataxia-telangiectasia mutated (ATM) kinase, and that this phosphorylation is important for cell cycle arrest and inhibition of apoptosis. 2 In addition, another group reported similar results in response to replicative stress. 3 Nevertheless, these findings were challenged by a third group, which demonstrated that in response to DNA damage BID −/− cells underwent cell cycle arrest and apoptosis in a manner indistinguishable from wild-type cells, arguing that BID is dispensable for the DDR.…”