Patients with Bloom's syndrome (BS) show a strong genetic instability and a predisposition to all types of cancer. Here, we report that the Bloom's syndrome protein (BLM) is cleaved in response to hydroxyurea (HU)- or UVC-induced apoptosis. The appearance and solubility of BLM proteolytic products differed according to whether proteolysis occurred in response to HU or UVC. One BS cell line homozygous for a null mutation in BLM was resistant to both UVC- and HU-induced apoptosis, while another one expressing a mutated BLM protein was resistant to HU-induced apoptosis but displayed normal sensitivity to UVC. Thus, UVC and HU appear to induce apoptosis through distinct pathways.