Negative control of CSL gene transcription by stress/DNA damage response and p53

ABSTRACTCSL is a key transcriptional repressor and mediator of Notch signaling. Despite wide interest in CSL, mechanisms responsible for its own regulation are little studied. CSL down-modulation in human dermal fibroblasts (HDFs) leads to conversion into cancer associated fibroblasts (CAF), promoting keratinocyte tumors. We show here that CSL transcript levels differ among HDF strains from different individuals, with negative correlation with genes involved in DNA damage/repair. CSL expression is negatively regulated by stress/DNA damage caused by UVA, Reactive Oxygen Species (ROS), smoke extract, and doxorubicin treatment. P53, a key effector of the DNA damage response, negatively controls CSL gene transcription, through suppression of CSL promoter activity and, indirectly, by increased p21 expression. CSL was previously shown to bind p53 suppressing its activity. The present findings indicate that p53, in turn, decreases CSL expression, which can serve to enhance p53 activity in acute DNA damage respon...