Selective cleavage of BLM, the Bloom syndrome protein, during apoptotic cell death

Bloom syndrome (BS) is an autosomal recessive disorder characterized by a h igh incidence of cancer and genomic instability. BLM, the protein defective in BS, is a RECQ-like helicase that is presumed to function in mammalian D NA replication, recombination, or repair. We show here that BLM, but not th e related RECQ-like helicase WRN, is rapidly cleaved in cells undergoing ap optosis. BLM was cleaved to 47- and 110-kDa major fragments, with kinetics similar to the apoptotic cleavage of poly(A)DP-ribose polymerase. BLM cleav age was prevented by a caspase 3 inhibitor and did not occur in caspase 3-d eficient cells. Moreover, recombinant BLM was cleaved to 47- and 110-kDa fr agments by caspase 3, but not caspase 6, in vitro. The caspase 3 recognitio n sequence (TEVD415)-T-412 was verified by mutating aspartate 415 to glycin e and showing that this mutation rendered BLM resistant to caspase 3 cleava ge. Cleavage did not abolish the BM helicase activity but abolished BLM nuc lear foci and the association of BLM with condensed DNA and the insoluble m atrix. The results suggest that BLM, but not WRN, is an early selected targ et during the execution of apoptosis.