Bid Plays a Role in the DNA Damage Response

A Matters Arising recently published in Cell by Kaufmann et al. (2007) concludes that the BH3-only Bid protein is dispensable for the DNA damage response. Based on our earlier findings that ATM-mediated Bid phosphorylation is essential for S phase arrest and for the regulation of apoptosis in response to DNA damage (Kamer et al., 2005; Zinkel et al., 2005), we would like to emphasize that we reached the opposite conclusion. Based on a careful comparison between the three studies (see below), we believe that the conclusion that Bid is dispensable for the DNA damage response is not supported by all of the available data. The Kaufmann et al. experiments evaluating DNA damage-induced apoptosis differ from our studies in several key aspects. First, the mouse embryonic fibro-blasts (MEFs) used by Kaufmann et al. most likely had DNA damage checkpoint response defects due to oncogene transformation (Bartkova et al., 2006; Di Micco et al., 2006). The hematopoietic cells they used were not homogeneous and many of these cells were not in cycle. Such cells are therefore less appropriate for studies of the molecular pathways regulated by ATM kinase and S phase-induced DNA damage. Our Kamer et al. (2005) study used MEFs immortalized using the catalytic subunit of telomerase (hTERT). In contrast, Kaufmann et al. (2007) used MEFs transformed with the oncogenes E1A and Ras. Kamer et al. found that hTERT-immortalized bid −/− MEFs were much less sensitive than bid +/+ MEFs to a variety of DNA-damaging reagents. Two other groups reported similar results using MEFs and neurons, respectively (Sax et al., 2002; Jacobs et al., 2007). The Zinkel et al. (2005) study used mouse hematopoietic cells that were in cycle, specifically Hox11-immortalized early myeloid progenitor cells (MPCs). In contrast, Kaufmann et al. (2007) used HoxB8-immortalized mouse fetal liver cells that displayed variable lineage and differentiation states (Perkins and Cory, 1993) as well as unfraction-ated mouse hematopoietic cells. Our Zinkel et al. (2005) study found that bid −/− but not bid +/+ MPCs and primary activated T cells were more sensitive to replicative stress-induced cell death. Importantly, our two groups found that the apoptotic response of bid −/− cells to DNA-damaging agents was rescued by rein-troduction of wild-type Bid, indicating that the observed differences in the apoptotic response between the bid −/− and bid +/+ cells were due to the absence of BID. We have demonstrated using multiple cell types and a variety …