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.
Larsen
Brian D
BD
Ottawa Hospital Research Institute, Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital, Ottawa, ON K1H 8L6, Canada.
Rampalli
Shravanti
S
Burns
Leanne E
LE
Brunette
Steve
S
Dilworth
F Jeffrey
FJ
Megeney
Lynn A
LA
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