Caspase 3/caspase-activated DNase promote cell differentiation by inducing DNA strand breaks

Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4230-5. doi: 10.1073/pnas.0913089107. Epub 2010 Feb 16.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Caspase 3 / metabolism*
  • Cell Differentiation*
  • Cell Line
  • Chromatin Immunoprecipitation
  • DNA Damage*
  • DNA Primers
  • Deoxyribonucleases / metabolism*
  • Enzyme Activation
  • Mice
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / enzymology
  • Muscle, Skeletal / metabolism

Substances

  • DNA Primers
  • Deoxyribonucleases
  • caspase-activated deoxyribonuclease
  • Caspase 3