SKIP counteracts p53-mediated apoptosis via selective regulation of p21Cip1 mRNA splicing.

Authors:
Yupeng Chen
Yupeng Chen
Brown University
United States
Lirong Zhang
Lirong Zhang
Zhengzhou University
China
Katherine A Jones
Katherine A Jones
The Salk Institute for Biological Studies
United States

Genes Dev 2011 Apr;25(7):701-16

Regulatory Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.

The Ski-interacting protein SKIP/SNW1 functions as both a splicing factor and a transcriptional coactivator for induced genes. We showed previously that transcription elongation factors such as SKIP are dispensable in cells subjected to DNA damage stress. However, we report here that SKIP is critical for both basal and stress-induced expression of the cell cycle arrest factor p21(Cip1). RNAi chromatin immunoprecipitation (RNAi-ChIP) and RNA immunoprecipitation (RNA-IP) experiments indicate that SKIP is not required for transcription elongation of the gene under stress, but instead is critical for splicing and p21(Cip1) protein expression. SKIP interacts with the 3' splice site recognition factor U2AF65 and recruits it to the p21(Cip1) gene and mRNA. Remarkably, SKIP is not required for splicing or loading of U2AF65 at other investigated p53-induced targets, including the proapoptotic gene PUMA. Consequently, depletion of SKIP induces a rapid down-regulation of p21(Cip1) and predisposes cells to undergo p53-mediated apoptosis, which is greatly enhanced by chemotherapeutic DNA damage agents. ChIP experiments reveal that SKIP is recruited to the p21(Cip1), and not PUMA, gene promoters, indicating that p21(Cip1) gene-specific splicing is predominantly cotranscriptional. The SKIP-associated factors DHX8 and Prp19 are also selectively required for p21(Cip1) expression under stress. Together, these studies define a new step that controls cancer cell apoptosis.
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http://dx.doi.org/10.1101/gad.2002611DOI ListingPossible
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3070933PMCFound
April 2011
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