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| 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. |
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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. |
Cancer and the bromodomains of BAF180. |
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PMID 22435813 |
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Targeted exome sequencing in clear cell renal cell carcinoma tumors suggests aberrant chromatin regulation as a crucial step in ccRCC development. |
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cDNA cloning of the human polybromo-1 gene on chromosome 3p21. |
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PMID 12487023 |
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PMID 11780067 |
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Molecular cloning of polybromo, a nuclear protein containing multiple domains including five bromodomains, a truncated HMG-box, and two repeats of a novel domain. |
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PMID 8917104 |
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The clinical significance of SWI/SNF complex in pancreatic cancer. |
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PMID 23229642 |
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Mammalian SWI/SNF complexes facilitate DNA double-strand break repair by promoting gamma-H2AX induction. |
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PMID 16932743 |
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Loss of PBRM1 expression is associated with renal cell carcinoma progression. |
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Int J Cancer. 2013 Jan 15;132(2):E11-7. doi: 10.1002/ijc.27822. Epub 2012 Oct 3. |
PMID 22949125 |
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BAP1 loss defines a new class of renal cell carcinoma. |
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PMID 22683710 |
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Convergent structural alterations define SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeler as a central tumor suppressive complex in pancreatic cancer. |
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PMID 22233809 |
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The spectrum of SWI/SNF mutations, ubiquitous in human cancers. |
Shain AH, Pollack JR. |
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PMID 23355908 |
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Polybromo-1: the chromatin targeting subunit of the PBAF complex. |
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PMID 19084573 |
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Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. |
Varela I, Tarpey P, Raine K, Huang D, Ong CK, Stephens P, Davies H, Jones D, Lin ML, Teague J, Bignell G, Butler A, Cho J, Dalgliesh GL, Galappaththige D, Greenman C, Hardy C, Jia M, Latimer C, Lau KW, Marshall J, McLaren S, Menzies A, Mudie L, Stebbings L, Largaespada DA, Wessels LF, Richard S, Kahnoski RJ, Anema J, Tuveson DA, Perez-Mancera PA, Mustonen V, Fischer A, Adams DJ, Rust A, Chan-on W, Subimerb C, Dykema K, Furge K, Campbell PJ, Teh BT, Stratton MR, Futreal PA. |
Nature. 2011 Jan 27;469(7331):539-42. doi: 10.1038/nature09639. Epub 2011 Jan 19. |
PMID 21248752 |
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Polybromo protein BAF180 functions in mammalian cardiac chamber maturation. |
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PMID 15601824 |
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SWI/SNF nucleosome remodellers and cancer. |
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PMID 21654818 |
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BAF180 is a critical regulator of p21 induction and a tumor suppressor mutated in breast cancer. |
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PMID 18339845 |
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The human SWI/SNF-B chromatin-remodeling complex is related to yeast rsc and localizes at kinetochores of mitotic chromosomes. |
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