PAF1 (Paf1, RNA polymerase II associated factor, homolog (S. cerevisiae))

2008-09-01   Shonali Deb , Moorthy P Ponnusamy , Surinder K Batra 

Department of Biochemistry, Molecular Biology University of Nebraska Medical Center 985870 Nebraska Medical Center Durham Research center 7005 Omaha, NE 68198-5870, USA

Identity

HGNC
LOCATION
19q13.2
LOCUSID
ALIAS
F23149_1,PD2
FUSION GENES

DNA/RNA

Atlas Image
Shows the genomic organization of Paf1 gene.

Description

The Paf1 gene is located on chromosome 19 in the q13.2 (loc126275) region, oriented from centromere to telomere, between the IgG binding protein gene (FcGBP) and the zinc-finger protein 36 gene (ZFP36). The Paf1 gene is 5178-bp long and contains 14 exons of sizes ranging from 30 to 551 bp. The first exon contains the 50-untranslated region, the translation start site, and the first 16 amino-acid residues. The last exon contains sequences that code for a domain rich in serine and aspartic acid residues and the 30-untranslated region. Introns range in size from 78 to 1539 bp. The sequences at the exon/intron boundaries are highly conserved with respect to canonical acceptor/donor site (AG/GT). The sequence of this gene is defined by 540 GenBank accessions from 506 cDNA clones, some from pancreas (seen 68 times), brain (51), ductal carcinoma, cell line (32), testis (23), lung (22), epithelioid carcinoma (20), placenta (20) and 151 other tissues.

Transcription

The complete PD2 cDNA sequence is present in the GenBankt/EBI Data Bank under the accession number, AJ401156. This sequence contains a 50-untranslated region of 156 bp upstream of the ATG translation initiation codon, and is flanked by a Kozak consensus sequence and a 30-untranslated region of 138 bp. The noncoding 30 region contains the polyadenylation signal, AATAAA. An open reading frame, from bp 157 to 1752, yields a predicted translation product of 59.9 kDa. Paf1 is overexpressed in the poorly differentiated pancreatic cancer cell line, Panc1. This gene is expressed at a very high level, 4.7 times the average gene in this release.

Proteins

Atlas Image
Schematic representation of protein structure and its organization. RRM, RNA recognition motif; RCC, regulator of chromosome condensation.

Description

There is a high degree of similarity between PD2 and the functional domains of DNA- and RNA-binding proteins. Paf1 protein possesses four myc-type helix-loop-helix, a leucine zipper, a DEAD-box subfamily ATP-dependent helicase domain, one eukaryotic RNA recognition motif (RRM) RNP-1 region signature, and a regulator of chromosome condensation (RCC1) signature. Two specific domains were also positioned toward the carboxyl-terminus: a glutamic acid rich domain, from amino acid 358 to 452, and a serine/aspartic acid-rich domain, from amino acid 402 to 531.

Expression

Paf1 is expressed at high levels in head, neck, liver, ovary and testis and at a low level in several other tissues including kidney.

Localisation

Paf1 is localized in the nucleus.

Function

It has been determined that hPaf1 is a subunit of the human PAF protein complex which was first identified during characterization of proteins associated with parafibromin. The hPAF complex interacts with the non-phosphorylated and Ser2- and Ser5-phosphorylated forms of the RNAP II large subunit, indicating its involvement in both transcription initiation and elongation. It has been shown that the establishment of H2B monoubiquitination is dependent on hPAF, the histone chaperone FACT and transcription. Further, the RNF20 / RNF40 UBCH6-PAF complex is required for transcription of the HOX genes in the following cascade: PAF - histone H2B ubiquitination - histone H3-K4 and H3-K79 methylation - HOX gene expression. Immunoprecipitation analysis has demonstrated that, found that RNA polymerase II associates with PAF1. Overexpression of hPaf1 in NIH3T3 cells results in enhanced growth rates in vitro and tumor formation in vivo.

Homology

There is a high degree of similarity between Paf1 and sequences from mouse (AK017762, AB041615, BC010317), Drosophila melanogaster (AY070561.1, AC008139, and AE003605), Caenorhabditis elegans (NP-505925, NM-073524 and CAB02869.1), Schizosaccharomyces pombe (CAB65804), and Saccharomyces cerevisiae (P38351). The human Paf1 shows 98% and 50% similarity to its rodent and Drosophila counterparts, respectively. The S. cerevisiae homologue corresponds to the widely investigated Paf1 protein, which shows 22% identity with the human sequence, and 44% similarity for a segment of 333 amino-acid residues that excluded the carboxyl terminus. Altogether, 22 amino acids are totally conserved among human, rodent, Drosophila, and S. cerevisiae, including two tyrosine residues. The least conserved domain is found in the carboxyl-terminal region. This domain is very rich in serine and aspartic acid residues.

Implicated in

Entity name
Various cancers
Disease
The hPaf1 overexpression is associated with various cancers as given below in the section of Oncogenesis. Although there is no direct association of Paf1 with any other disease, parafibromin, which is part of the hPAF complex, is encoded by the HRPT2 gene and is implicated in suppression of the hyperparathyroidism-jaw tumor (HPT-JT) syndrome . The HRPT2 gene is mutated in the germ line of HPT-JT patients.
Oncogenesis
The oncogenic property of hPaf1 has been reported. Overexpression of hPaf1 in NIH3T3 cells results in enhanced growth rates in vitro and tumor formation in vivo. Further, hPaf1 overexpression is associated with different cancers, including leukemia, lung, myeloma and fallopian tube and testicular carcinoma. In cell lines, hPaf1 is overexpressed due to gene amplification in the poorly differentiated pancreatic cancer cell line, Panc1.

Bibliography

Pubmed IDLast YearTitleAuthors
151964602004Facts about FACT and transcript elongation through chromatin.Belotserkovskaya R et al
175990572007Human RNA polymerase II-associated factor complex: dysregulation in cancer.Chaudhary K et al
164911292006The human homologue of the RNA polymerase II-associated factor 1 (hPaf1), localized on the 19q13 amplicon, is associated with tumorigenesis.Moniaux N et al
162467182005From transcription to mRNA: PAF provides a new path.Rosonina E et al
156320632005The parafibromin tumor suppressor protein is part of a human Paf1 complex.Rozenblatt-Rosen O et al
159236222005The HRPT2 tumor suppressor gene product parafibromin associates with human PAF1 and RNA polymerase II.Yart A et al
160246562005The human PAF complex coordinates transcription with events downstream of RNA synthesis.Zhu B et al
163079232005Monoubiquitination of human histone H2B: the factors involved and their roles in HOX gene regulation.Zhu B et al

Other Information

Locus ID:

NCBI: 54623
MIM: 610506
HGNC: 25459
Ensembl: ENSG00000006712

Variants:

dbSNP: 54623
ClinVar: 54623
TCGA: ENSG00000006712
COSMIC: PAF1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000006712ENST00000221265Q8N7H5
ENSG00000006712ENST00000221265A0A024R0H6
ENSG00000006712ENST00000416728B4DGJ5
ENSG00000006712ENST00000595379M0QYC7
ENSG00000006712ENST00000595564Q8N7H5

Expression (GTEx)

0
50
100
150
200

Pathways

PathwaySourceExternal ID
Metabolism of proteinsREACTOMER-HSA-392499
Post-translational protein modificationREACTOMER-HSA-597592
Gene ExpressionREACTOMER-HSA-74160
RNA Polymerase II TranscriptionREACTOMER-HSA-73857
RNA Polymerase II Pre-transcription EventsREACTOMER-HSA-674695
RNA Polymerase II Transcription ElongationREACTOMER-HSA-75955
Formation of RNA Pol II elongation complexREACTOMER-HSA-112382
Protein ubiquitinationREACTOMER-HSA-8852135
E3 ubiquitin ligases ubiquitinate target proteinsREACTOMER-HSA-8866654

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
163079232005Monoubiquitination of human histone H2B: the factors involved and their roles in HOX gene regulation.192
201787422010The human PAF1 complex acts in chromatin transcription elongation both independently and cooperatively with SII/TFIIS.129
205414772010The PAF complex synergizes with MLL fusion proteins at HOX loci to promote leukemogenesis.93
266590562015RNA polymerase II-associated factor 1 regulates the release and phosphorylation of paused RNA polymerase II.67
262791882015PAF1, a Molecular Regulator of Promoter-Proximal Pausing by RNA Polymerase II.63
241014742013Structural basis for Spt5-mediated recruitment of the Paf1 complex to chromatin.38
164911292006The human homologue of the RNA polymerase II-associated factor 1 (hPaf1), localized on the 19q13 amplicon, is associated with tumorigenesis.35
288704252017Emerging Insights into the Roles of the Paf1 Complex in Gene Regulation.33
224519212012Histone H3R17me2a mark recruits human RNA polymerase-associated factor 1 complex to activate transcription.32
230083332012A role for the RNA pol II-associated PAF complex in AID-induced immune diversification.32

Citation

Shonali Deb ; Moorthy P Ponnusamy ; Surinder K Batra

PAF1 (Paf1, RNA polymerase II associated factor, homolog (S. cerevisiae))

Atlas Genet Cytogenet Oncol Haematol. 2008-09-01

Online version: http://atlasgeneticsoncology.org/gene/44202/paf1