The p53 tumor suppressor protein represses human snRNA gene transcription by RNA polymerases II and III independently of sequence-specific DNA binding.
Journal: 2005/May - Molecular and Cellular Biology
ISSN: 0270-7306
Abstract:
Human U1 and U6 snRNA genes are transcribed by RNA polymerases II and III, respectively. While the p53 tumor suppressor protein is a general repressor of RNA polymerase III transcription, whether p53 regulates snRNA gene transcription by RNA polymerase II is uncertain. The data presented herein indicate that p53 is an effective repressor of snRNA gene transcription by both polymerases. Both U1 and U6 transcription in vitro is repressed by recombinant p53, and endogenous p53 occupancy at these promoters is stimulated by UV light. In response to UV light, U1 and U6 transcription is strongly repressed. Human U1 genes, but not U6 genes, contain a high-affinity p53 response element located within the core promoter region. Nonetheless, this element is not required for p53 repression and mutant p53 molecules that do not bind DNA can maintain repression, suggesting a reliance on protein interactions for p53 promoter recruitment. Recruitment may be mediated by the general transcription factors TATA-box binding protein and snRNA-activating protein complex, which interact well with p53 and function for both RNA polymerase II and III transcription.
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Mol Cell Biol 25(8): 3247-3260

The p53 Tumor Suppressor Protein Represses Human snRNA Gene Transcription by RNA Polymerases II and III Independently of Sequence-Specific DNA Binding

Department of Biochemistry & Molecular Biology, Michigan State University, East Lansing, Michigan
Corresponding author. Mailing address: Department of Biochemistry & Molecular Biology, Michigan State University, East Lansing, MI 48824. Phone: (517) 353-3980. Fax: (517) 353-9334. E-mail: ude.usm@wryrneh.
Received 2004 Sep 7; Revised 2004 Oct 28; Accepted 2005 Jan 20.

Abstract

Human U1 and U6 snRNA genes are transcribed by RNA polymerases II and III, respectively. While the p53 tumor suppressor protein is a general repressor of RNA polymerase III transcription, whether p53 regulates snRNA gene transcription by RNA polymerase II is uncertain. The data presented herein indicate that p53 is an effective repressor of snRNA gene transcription by both polymerases. Both U1 and U6 transcription in vitro is repressed by recombinant p53, and endogenous p53 occupancy at these promoters is stimulated by UV light. In response to UV light, U1 and U6 transcription is strongly repressed. Human U1 genes, but not U6 genes, contain a high-affinity p53 response element located within the core promoter region. Nonetheless, this element is not required for p53 repression and mutant p53 molecules that do not bind DNA can maintain repression, suggesting a reliance on protein interactions for p53 promoter recruitment. Recruitment may be mediated by the general transcription factors TATA-box binding protein and snRNA-activating protein complex, which interact well with p53 and function for both RNA polymerase II and III transcription.

Abstract

The p53 tumor suppressor protein plays a critical role in preventing unwarranted cellular proliferation by activating transcription of key target genes that influence cell growth and apoptosis (reviewed in references 28, 31, 35, and 64). Though p53 can enable both pathways, the switch controlling which cellular outcome is enacted is uncertain (reviewed in references 65 and 66), but both the p53 level and the nature of the DNA damage can influence apoptotic response (8). Altogether, p53 activity serves to prevent passage of mutations to daughter cells after DNA damage.

Recent evidence suggests that p53 regulates transcription of genes that are not obviously involved in controlling cell cycle arrest or apoptosis. Indeed, p53 can repress RNA polymerase I (3, 72) and III (5, 9) transcription of genes encoding a variety of nontranslated RNAs that play critical roles at numerous points during global gene expression. RNA polymerase III activity is elevated in p53 knockout fibroblasts (5) and in a variety of cancer-derived cell lines that lack p53 function (57). However, the mechanism for p53 regulation of RNA polymerase III transcription is controversial. A kinetic analysis of RNA polymerase III repression using p53 expressed from a stably integrated inducible p53 gene suggested that RNA polymerase III repression is mediated indirectly through p53-dependent degradation of TFIIIB (11). In contrast, recombinant p53 can repress in vitro transcription from a variety of RNA polymerase III-specific promoters and can interact with components of the general transcription machinery required for RNA polymerase III transcription (5, 9, 10, 58), indicating that p53 might directly repress transcription by RNA polymerase III.

Within the group of genes transcribed by RNA polymerase III, the human snRNA gene family is intriguing because these genes contain similar sets of promoter elements, and yet only some genes are transcribed by RNA polymerase III while others are transcribed by RNA polymerase II (see references 19, 23, 24, and 42 for review). Regardless of polymerase specificity, human snRNA genes contain a distal sequence element in the upstream promoter region that serves as the recognition element for activator proteins, including Oct-1, STAF, and Sp1 (33, 54). These factors activate transcription from the core promoters that commonly contain a proximal sequence element (PSE). The PSE is directly recognized by a general transcription factor called the snRNA activating protein complex (SNAPC) (52), which is also known as the PSE transcription factor (49). SNAPC is involved in human snRNA gene transcription by both RNA polymerases II and III (20-22, 51, 69). RNA polymerase III-transcribed snRNA genes also contain a TATA box that serves to recruit the TATA-box binding protein (TBP) as part of an snRNA-specific TFIIIB complex (45, 55, 60).

The conservation of important promoter elements among human snRNA genes suggests that transcription of these genes by RNA polymerases II and III may be coordinately regulated. However, it is not known whether p53 can regulate human snRNA gene transcription by RNA polymerase II. A role for p53 in this process is suggested from two sources. Firstly, in response to UV light treatment, human U1 and U2 snRNA genes exhibit a delayed and prolonged reduction in transcription by RNA polymerase II (14, 47, 48). In part, this reduction may be attributable to increased hyperphosphorylation of the carboxy-terminal domain of the RNA polymerase II largest subunit in response to UV light (27). However, in normal human diploid fibroblasts, the balance of hyper- and hypophosphorylated RNA polymerase II is restored by 6 h after UV light treatment (46), suggesting additional cellular mechanisms that enable snRNA gene repression after UV light exposure. Potentially, p53 activation by DNA damage might play a direct role in the prolonged repression of these genes.

Secondly, infection of human cells by adenovirus serotype 12 causes metaphase fragility at four chromosomal sites, including the U1 snRNA (RNU1) and U2 snRNA (RNU2) loci (1, 36), in a process that requires p53 (38, 39). It was postulated that fragile site formation occurs during viral infection, because RNA polymerase II stalls at these genes and interferes with chromosome condensation during metaphase (37). Interestingly, p53 that harbors mutations in the DNA binding domain supports fragile site formation (39), and overexpression of the C-terminal domain of p53 alone, which lacks the DNA binding domain, induces fragility during transient transfection (71). Together, these data indicate that p53 is important for generation of fragile sites at the U1 and U2 snRNA gene loci and may play a role in regulation of these genes in a fashion that does not require sequence-specific binding of p53 to DNA.

In this study, the role of p53 in governing human snRNA gene transcription by RNA polymerase II and III was examined. We show that recombinant p53 represses both U1 and U6 transcription by RNA polymerase II and III, respectively. Repression is supported by the C-terminal region of p53 alone, indicating that sequence-specific DNA binding by p53 is not critical for repression. Both the full-length and C terminus of p53 alone can associate with the U1 and U6 promoters during repression, and promoter recruitment may be assisted through interactions with the general transcription factors SNAPC and TBP, which are commonly required for transcription of both U1 and U6 snRNA genes. In vivo, p53 can bind to both U1 and U6 snRNA genes in untreated human MCF-7 cells, and promoter occupancy is stimulated after UV light treatment. These results further indicate that p53 contributes to snRNA gene regulation in response to DNA damage.

Acknowledgments

The anti-galectin-3 antibody (Mac2) was a gift from John Wang (Michigan State University). The pRc/RSV and pRc/RSV-p53-Flag.wt plasmids were a gift from Roland Kwok (University of Michigan). We thank Liping Gu, Gauri Jawdekar, Min-Hao Kuo, and Jim Geiger for critical assessment of the manuscript and appreciate the technical assistance provided by Craig Hinkley, Brandon LaMere, Xianzhou Song, and Tharakeswari Selvakumar. We acknowledge the National Cell Culture Center for preparation of HeLa cells.

This work was supported by an NIH grant (GM59805) to R.W.H.

Acknowledgments

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