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

Yupeng Chen
Yupeng Chen
Brown University
United States
Lirong Zhang
Lirong Zhang
Zhengzhou University
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.
PDF Download - Full Text Link
( Please be advised that this article is hosted on an external website not affiliated with
Source Status ListingPossible
April 2011
2 Reads

Similar Publications

SKIP interacts with c-Myc and Menin to promote HIV-1 Tat transactivation.

Mol Cell 2009 Oct;36(1):75-87

Regulatory Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037-1099, USA.

The Ski-interacting protein SKIP/SNW1 associates with the P-TEFb/CDK9 elongation factor and coactivates inducible genes, including HIV-1. We show here that SKIP also associates with c-Myc and Menin, a subunit of the MLL1 histone methyltransferase (H3K4me3) complex and that HIV-1 Tat transactivation requires c-Myc and Menin, but not MLL1 or H3K4me3. RNAi-ChIP experiments reveal that SKIP acts downstream of Tat:P-TEFb to recruit c-Myc and its partner TRRAP, a scaffold for histone acetyltransferases, to the HIV-1 promoter. Read More

View Article
October 2009

Gene-specific requirement for P-TEFb activity and RNA polymerase II phosphorylation within the p53 transcriptional program.

Genes Dev 2006 Mar;20(5):601-12

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

Activation of the p53 pathway mediates cellular responses to diverse forms of stress. Here we report that the p53 target gene p21(CIP1) is regulated by stress at post-initiation steps through conversion of paused RNA polymerase II (RNAP II) into an elongating form. High-resolution chromatin immunoprecipitation assays (ChIP) demonstrate that p53-dependent activation of p21(CIP1) transcription after DNA damage occurs concomitantly with changes in RNAP II phosphorylation status and recruitment of the elongation factors DSIF (DRB Sensitivity-Inducing Factor), P-TEFb (Positive Transcription Elongation Factor b), TFIIH, TFIIF, and FACT (Facilitates Chromatin Transcription) to distinct regions of the p21(CIP1) locus. Read More

View Article
March 2006

Stress-induced expression of p53 target genes is insensitive to SNW1/SKIP downregulation.

Cell Mol Biol Lett 2011 Sep 3;16(3):373-84. Epub 2011 Apr 3.

Department of Cell Biology, Faculty of Science, Charles University in Prague, Vinicna 7, 12843, Prague, Czech Republic.

Pharmacological inhibition of protein kinases that are responsible for the phosphorylation of the carboxy-terminal domain (CTD) of RNA Pol II during transcription by 5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole (DRB) leads to severe inhibition of mRNA synthesis and activates p53. Transcription of the p53 effectors that are induced under these conditions, such as p21 or PUMA, must bypass the requirement for CTD phosphorylation by the positive elongation factor P-TEFb. Here, we have downregulated SNW1/SKIP, a splicing factor and a transcriptional co-regulator, which was found to interact with P-TEFb and synergistically affect Tat-dependent transcription elongation of HIV 1. Read More

View Article
September 2011

Myc suppression of the p21(Cip1) Cdk inhibitor influences the outcome of the p53 response to DNA damage.

Nature 2002 Oct 2;419(6908):729-34. Epub 2002 Oct 2.

Cell Biology Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.

Activation of the tumour suppressor p53 by DNA damage induces either cell cycle arrest or apoptotic cell death. The cytostatic effect of p53 is mediated by transcriptional activation of the cyclin-dependent kinase (CDK) inhibitor p21(Cip1), whereas the apoptotic effect is mediated by transcriptional activation of mediators including PUMA and PIG3 (ref. 2). Read More

View Article
October 2002