Caspase-6 gene disruption reveals a requirement for lamin A cleavage in apoptotic chromatin condensation

To study the role of caspase‐6 during nuclear disassembly, we generated a chicken DT40 cell line in which both alleles of the caspase‐6 gene were disrupted. No obvious morphological differences were observed in the apoptotic process in caspase‐6‐ deficient cells compared with the wild type. However, examination of apoptosis in a cell‐free system revealed a block in chromatin condensation and apoptotic body formation when nuclei from HeLa cells expressing lamin A or lamin A‐transfected Jurkat cells were incubated in caspase‐6‐deficient apoptotic extracts. Transfection of exogenous caspase‐6 into the clone reversed this phenotype. Lamins A and C, which are caspase‐6‐only substrates, were cleaved by the wild‐type and heterozygous apoptotic extracts but not by the extracts lacking caspase‐6. Furthermore, the caspase‐6 inhibitor z‐VEID‐fmk mimicked the effects of caspase‐6 deficiency and prevented the cleavage of lamin A. Taken together, these observations indicate that caspase‐6 activity is essential for lamin A cleavage and that when lamin A is present it must be cleaved in order for the chromosomal DNA to undergo complete condensation during apoptotic execution.