PBRM1 (polybromo 1)

2013-03-01   Rafal Pawlowski 

Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland

Identity

HGNC
LOCATION
3p21.1
IMAGE
Atlas Image
LEGEND
Location of PBRM1 gene on chromosome 3 p21.1. PBRM1 gene is indicated in red, neighbouring genes in blue. Arrows indicate direction.
LOCUSID
ALIAS
BAF180,PB1
FUSION GENES

DNA/RNA

Atlas Image
The exon-intron organisation of the PBRM1 gene. Exons are shown as dark blue boxes and broken lines connecting the exons indicate introns. Exon and intron sizes are in scale.

Description

PBRM1 gene is located on chromosome 3p21.1 and spans 140566 base pairs on the minus DNA strand.

Transcription

20 transcripts have been annotated for the PBRM1 gene (according to Ensembl as of February 2013), which consists of 30 exons.

Pseudogene

PBRM1 pseudogenes are not known.

Proteins

Atlas Image
Schematic diagram of the PBRM1 (BAF180) protein. BD1-6: bromodomain 1-6; BAH1 and BAH2: bromo-adjacent homology domains 1 and 2; HMG: high mobility group domain.

Description

Human PBRM1 gene encodes an 1582 amino acid protein, also referred to as BAF180. Six bromodomains (BD1-6), known to recognize acetylated lysine residues and frequently found in chromatin-associated proteins, constitute the N-terminal half of PBRM1. The C-terminal half of PBRM1 contains two bromo-adjacent homology (BAH) domains (BAH1 and BAH2), present in some proteins involved in transcription regulation. High mobility group (HMG) domain is located close to the C-terminus of PBRM1. HMG domains are found in a number of factors regulating DNA-dependent processes where HMG domains often mediate interactions with DNA.

Expression

PBRM1 is ubiquitously expressed during mouse embryonic development (Wang et al., 2004), and has been detected in various human tissues including pancreas, kidney, skeletal muscle, liver, lung, placenta, brain, heart, intestine, ovaries, testis, prostate, thymus and spleen (Xue et al., 2000; Horikawa and Barrett, 2002).

Localisation

PBRM1 protein localises to the nucleus of cells (Nicolas and Goodwin, 1996). As a component of the PBAF chromatin-remodelling complex, it associates with chromatin (Thompson, 2009), and has been reported to confer the localisation of PBAF complex to the kinetochores of mitotic chromosomes (Xue et al., 2000).

Function

PBRM1/BAF180 functions in the regulation of gene expression as a constituent of the evolutionary-conserved SWI/SNF chromatin remodelling complexes (Euskirchen et al., 2012). Beside BRD7 and BAF200, PBRM1 is one of the unique components of the SWI/SNF-B complex also known as polybromo/BRG1-associated factors (or PBAF), absent in the SWI/SNF-A (BAF) complex (Xue et al., 2000; Brownlee et al., 2012). On that account, and because it contains bromodomains known to mediate binding to acetylated histones, PBRM1 has been postulated to target PBAF complex to specific chromatin sites, therefore providing the functional selectivity for the complex (Xue et al., 2000; Lemon et al., 2001; Brownlee et al., 2012). Although direct evidence for PBRM1 involvement is lacking, SWI/SNF complexes have also been shown to play a role in DNA damage response (Park et al., 2006).
In vivo studies have shown that PBRM1 deletion leads to embryonic lethality in mice, where PBRM1 is required for mammalian cardiac chamber maturation and coronary vessel formation (Wang et al., 2004; Huang et al., 2008).
More recently, PBRM1 has acceded the continuously growing group of SWI/SNF subunits frequently mutated in cancer (Wilson and Roberts, 2011; Shain and Pollack, 2013). PBRM1 mutations are most predominant in renal cell carcinomas detected in over 40% of cases, placing PBRM1 second (after VHL) on the list of most frequently mutated genes in this cancer (Varela et al., 2011; Hakimi et al., 2013; Peña-Llopis et al., 2012; Pawlowski et al., 2013). PBRM1 mutations have also been found in a smaller group of breast and pancreatic cancers (Xia et al., 2008; Shain et al., 2012; Numata et al., 2013). Therefore, PBRM1 is considered a novel tumour suppressor in these cancers.

Homology

PBRM1 protein is highly conserved across animal kingdom, from flies and worms though all vertebrates to humans.

Mutations

Germinal

Germinal mutations of PBRM1 have not been reported.

Somatic

PBRM1 mutations have been found in a large fraction of clear cell renal cell carcinomas (Varela et al., 2011; Duns et al., 2012; Hakimi et al., 2013), and to a smaller extend also in breast (Xia et al., 2008; Shain and Pollack, 2013) and pancreatic cancers (Numata et al., 2013; Shain and Pollack, 2013). The vast majority of PBRM1 mutations found in renal and breast cancers are truncating (nonsense, frameshift insertions and deletions) (Varela et al., 2011; Hakimi et al., 2013).

Implicated in

Entity name
Renal cell carcinoma (RCC)
Note
PBRM1 mutations and/or loss of protein expression have been reported in a large portion of clear cell subtype of RCC (Varela et al., 2011; Duns et al., 2012; Hakimi et al., 2013; Peña-Llopis et al., 2012; Pawlowski et al., 2013). Therefore, PBRM1 has been postulated to function as a tumour suppressor and the second major RCC cancer gene after VHL. PBRM1 mutations are largely mutually exclusive with BAP1 mutations (Peña-Llopis et al., 2012; Kapur et al., 2013).
Prognosis
PBRM1 mutations are more common in patients with advance stages (Hakimi et al., 2013) and loss of PBRM1 protein expression has been associated with advanced tumour stage, low differentiation grade and worse patient outcome (Pawlowski et al., 2013). In another study, no correlation between PBRM1 status and tumour grade was found (Peña-Llopis et al., 2012). Although PBRM1-mutant tumours are associated with better prognosis than BAP1-mutant tumours, tumours mutated for both PBRM1 and BAP1 exhibit the greatest aggressiveness (Kapur et al., 2013).
Entity name
Breast cancer
Note
Truncating mutations have been identified in a minority of breast cancers (Xia et al., 2008). In their study, authors showed inhibition of cell proliferation upon PBRM1 re-introduction into a mutant cell line, thus providing direct evidence for tumour suppressing role of PBRM1 in breast cancer.
Entity name
Pancreatic cancer
Note
Mutations in PBRM1 have been reported in a small fraction of pancreatic cancer samples (Numata et al., 2013).

Bibliography

Pubmed IDLast YearTitleAuthors
224358132012Cancer and the bromodomains of BAF180.Brownlee PM et al
224613742012Targeted exome sequencing in clear cell renal cell carcinoma tumors suggests aberrant chromatin regulation as a crucial step in ccRCC development.Duns G et al
229522402012SWI/SNF chromatin-remodeling factors: multiscale analyses and diverse functions.Euskirchen G et al
230365772013Clinical and pathologic impact of select chromatin-modulating tumor suppressors in clear cell renal cell carcinoma.Hakimi AA et al
124870232002cDNA cloning of the human polybromo-1 gene on chromosome 3p21.Horikawa I et al
185080412008Coronary development is regulated by ATP-dependent SWI/SNF chromatin remodeling component BAF180.Huang X et al
233331142013Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation.Kapur P et al
117800672001Selectivity of chromatin-remodelling cofactors for ligand-activated transcription.Lemon B et al
89171041996Molecular cloning of polybromo, a nuclear protein containing multiple domains including five bromodomains, a truncated HMG-box, and two repeats of a novel domain.Nicolas RH et al
232296422013The clinical significance of SWI/SNF complex in pancreatic cancer.Numata M et al
169327432006Mammalian SWI/SNF complexes facilitate DNA double-strand break repair by promoting gamma-H2AX induction.Park JH et al
229491252013Loss of PBRM1 expression is associated with renal cell carcinoma progression.Pawłowski R et al
226837102012BAP1 loss defines a new class of renal cell carcinoma.Peña-Llopis S et al
222338092012Convergent structural alterations define SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeler as a central tumor suppressive complex in pancreatic cancer.Shain AH et al
233559082013The spectrum of SWI/SNF mutations, ubiquitous in human cancers.Shain AH et al
190845732009Polybromo-1: the chromatin targeting subunit of the PBAF complex.Thompson M et al
212487522011Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma.Varela I et al
156018242004Polybromo protein BAF180 functions in mammalian cardiac chamber maturation.Wang Z et al
216548182011SWI/SNF nucleosome remodellers and cancer.Wilson BG et al
183398452008BAF180 is a critical regulator of p21 induction and a tumor suppressor mutated in breast cancer.Xia W et al
110785222000The human SWI/SNF-B chromatin-remodeling complex is related to yeast rsc and localizes at kinetochores of mitotic chromosomes.Xue Y et al

Other Information

Locus ID:

NCBI: 55193
MIM: 606083
HGNC: 30064
Ensembl: ENSG00000163939

Variants:

dbSNP: 55193
ClinVar: 55193
TCGA: ENSG00000163939
COSMIC: PBRM1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000163939ENST00000296302Q86U86
ENSG00000163939ENST00000337303Q86U86
ENSG00000163939ENST00000356770Q86U86
ENSG00000163939ENST00000394830Q86U86
ENSG00000163939ENST00000409057Q86U86
ENSG00000163939ENST00000409114Q86U86
ENSG00000163939ENST00000409767Q86U86
ENSG00000163939ENST00000410007Q86U86
ENSG00000163939ENST00000412587Q86U86
ENSG00000163939ENST00000420148C9JQF1
ENSG00000163939ENST00000423351E7EVG2
ENSG00000163939ENST00000424867C9J9L6
ENSG00000163939ENST00000431678C9JPI5
ENSG00000163939ENST00000439181C9J409
ENSG00000163939ENST00000446103H0Y5B5
ENSG00000163939ENST00000449505C9J053
ENSG00000163939ENST00000450271C9JCJ2
ENSG00000163939ENST00000458294C9J409

Expression (GTEx)

0
5
10
15
20
25
30

Pathways

PathwaySourceExternal ID
Chromatin organizationREACTOMER-HSA-4839726
Chromatin modifying enzymesREACTOMER-HSA-3247509
RMTs methylate histone argininesREACTOMER-HSA-3214858

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
212487522011Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma.462
241855092013Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas.183
233331142013Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation.124
183398452008BAF180 is a critical regulator of p21 induction and a tumor suppressor mutated in breast cancer.67
206607292010Polybromo-associated BRG1-associated factor components BRD7 and BAF180 are critical regulators of p53 required for induction of replicative senescence.64
240296452014Radiogenomics of clear cell renal cell carcinoma: associations between CT imaging features and mutations.64
210372402011Most genome-wide significant susceptibility loci for schizophrenia and bipolar disorder reported to date cross-traditional diagnostic boundaries.63
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
241669832014Clinical and pathological impact of VHL, PBRM1, BAP1, SETD2, KDM6A, and JARID1c in clear cell renal cell carcinoma.46
229491252013Loss of PBRM1 expression is associated with renal cell carcinoma progression.45

Citation

Rafal Pawlowski

PBRM1 (polybromo 1)

Atlas Genet Cytogenet Oncol Haematol. 2013-03-01

Online version: http://atlasgeneticsoncology.org/gene/43697/pbrm1