Caspase 3/caspase-activated DNase promote cell differentiation by inducing DNA strand breaks.
Caspase 3 is required for the differentiation of a wide variety of cell types, yet it remains unclear how this apoptotic protein could promote such a cell-fate decision. Caspase signals often result in the activation of the specific nuclease caspase-activated DNase (CAD), suggesting that cell differentiation may be dependent on a CAD-mediated modification in chromatin structure. In this study, we have investigated if caspase 3/CAD plays a role in initiating the DNA strand breaks that are known to occur during the terminal differentiation of skeletal muscle cells. Here, we show that inhibition of caspase 3 or reduction of CAD expression leads to a dramatic loss of strand-break formation and a block in the myogenic program. Caspase-dependent induction of differentiation results in CAD targeting of the p21 promoter, and loss of caspase 3 or CAD leads to a significant down-regulation in p21 expression. These results show that caspase 3/CAD promotes cell differentiation by directly modifying the DNA/nuclear microenvironment, which enhances the expression of critical regulatory genes.
Ottawa Hospital Research Institute, Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital, Ottawa, ON K1H 8L6, Canada.
Brian D
BD
Larsen
Shravanti
S
Rampalli
Leanne E
LE
Burns
Steve
S
Brunette
F Jeffrey
FJ
Dilworth
Lynn A
LA
Megeney
D000818:Animals; D001483:Base Sequence; D053148:Caspase 3 / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D004249:DNA Damage; D017931:DNA Primers; D003851:Deoxyribonucleases / Q000378:metabolism*; D004789:Enzyme Activation; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology / Q000201:enzymology / Q000378:metabolism
D017931:DNA Primers; D003851:Deoxyribonucleases; C109663:caspase-activated deoxyribonuclease; D053148:Caspase 3