Sirt1 antagonizes Stra13 Mediated p53 Acetylation and Senescence

Abstract

Stra13 is a basic helix-loop-helix transcription factor which functions as a positive regulator of p53 dependant senescence. However, the underlying mechanism of how Stra13 modulates senescence is not fully understood. On the other hand, Sirt1 is a NAD+-dependent histone deacetylase that catalyses the deacetylation of mouse p53 at lysine 379. Deacetylation of p53 generally destabilizes and inactivates p53 including its ability to induce senescence. We hypothesize that Stra13 and Sirt1 antagonizes each other to regulate p53 functions. We demonstrate that Stra13 gain of function increases p53 mediated senescence and p53 acetylation at lysine 379. Ectopic expression or activity modulation of Sirt1 counteracts Stra13 mediated p53 acetylation and senescence. Interaction studies further revealed that under cellular stress, Sirt1 dissociates from the Stra13 and p53 while p53-Stra13 interaction is strengthened. Our findings provide new insights to the modulation of p53 mediated cellular senescence via antagonism of Sirt1 and Stra13.