PBRM1 explained

Protein polybromo-1 (PB1) also known as BRG1-associated factor 180 (BAF180) is a protein that in humans is encoded by the PBRM1 gene.^{[1] [2] [3]}

Structure and function

Human PBRM1 is one of three unique components of the SWI/SNF-B (PBAF) chromatin-remodeling complex, which contains at least SMARCA4/BRG1, SMARCB1/SNF5/INI1/BAF47, ACTL6A/BAF53A or ACTL6B/BAF53B, SMARCE1/BAF57, SMARCD1/BAF60A, SMARCD2/BAF60B, and actin.^{[4] [5]}

Chicken PB1 possesses 5 bromodomains, 2 bromo-adjacent homology (BAH) domains, and 1 truncated high-mobility group (HMG) motif. cPB1 is also homologous to yeast Rsc1, Rsc2, and Rsc4, essential proteins that are required for cell cycle progression through mitosis.^[1]

Clinical significance

PBRM1 is thought to be a tumor suppressor gene in many cancer subtypes largely due to the mutational pattern.^[6] Most notably, mutations and copy number alterations in PBRM1 are highly prevalent in clear cell renal cell carcinoma (ccRCC).^[7]

Role renal carcinoma

Loss of function mutations in PBRM1 often co-occur with loss of function mutations in the VHL gene in clear cell renal cell carcinoma (ccRCC).^[8] The inactivation of PBRM1 in combination with biallelic loss of VHL has been shown to potentiate HIF1α signaling and activate the pro-tumorigenic NF-κB pathway.^{[9] [10]} Genetic loss of PBRM1 is thought to underlie the early initiation of ccRCC due to the sufficiency of conditional deletion of Pbrm1 and Vhl for renal carcinomagenesis in mice.^[11] While several studies have identified a favorable outcomes among advanced ccRCC cases with PBRM1 mutations when treated with immune checkpoint inhibitors, there is still debate about the utility of PBRM1 status as a biomarker for response to ICI therapy.^{[12] [13]}

Further reading

• Martens JA, Winston F . Recent advances in understanding chromatin remodeling by Swi/Snf complexes . Current Opinion in Genetics & Development . 13 . 2 . 136–142 . April 2003 . 12672490 . 10.1016/S0959-437X(03)00022-4 .
• Suzuki H, Fukunishi Y, Kagawa I, Saito R, Oda H, Endo T, Kondo S, Bono H, Okazaki Y, Hayashizaki Y . 6 . Protein-protein interaction panel using mouse full-length cDNAs . Genome Research . 11 . 10 . 1758–1765 . October 2001 . 11591653 . 311163 . 10.1101/gr.180101 . vanc .
• Lemon B, Inouye C, King DS, Tjian R . Selectivity of chromatin-remodelling cofactors for ligand-activated transcription . Nature . 414 . 6866 . 924–928 . 2002 . 11780067 . 10.1038/414924a . 4391100 .
• Olave I, Wang W, Xue Y, Kuo A, Crabtree GR . Identification of a polymorphic, neuron-specific chromatin remodeling complex . Genes & Development . 16 . 19 . 2509–2517 . October 2002 . 12368262 . 187451 . 10.1101/gad.992102 . vanc .
• Horikawa I, Barrett JC . cDNA cloning of the human polybromo-1 gene on chromosome 3p21 . DNA Sequence . 13 . 4 . 211–215 . August 2002 . 12487023 . 10.1080/1042517021000021590 . 23406882 .
• Sekine I, Sato M, Sunaga N, Toyooka S, Peyton M, Parsons R, Wang W, Gazdar AF, Minna JD . 6 . The 3p21 candidate tumor suppressor gene BAF180 is normally expressed in human lung cancer . Oncogene . 24 . 16 . 2735–2738 . April 2005 . 15735765 . 10.1038/sj.onc.1207694 . 19875372 . vanc .
• Yan Z, Cui K, Murray DM, Ling C, Xue Y, Gerstein A, Parsons R, Zhao K, Wang W . 6 . PBAF chromatin-remodeling complex requires a novel specificity subunit, BAF200, to regulate expression of selective interferon-responsive genes . Genes & Development . 19 . 14 . 1662–1667 . July 2005 . 15985610 . 1176002 . 10.1101/gad.1323805 . vanc .
• Tao WA, Wollscheid B, O'Brien R, Eng JK, Li XJ, Bodenmiller B, Watts JD, Hood L, Aebersold R . 6 . Quantitative phosphoproteome analysis using a dendrimer conjugation chemistry and tandem mass spectrometry . Nature Methods . 2 . 8 . 591–598 . August 2005 . 16094384 . 10.1038/nmeth776 . vanc . 20475874 .
• Beausoleil SA, Villén J, Gerber SA, Rush J, Gygi SP . A probability-based approach for high-throughput protein phosphorylation analysis and site localization . Nature Biotechnology . 24 . 10 . 1285–1292 . October 2006 . 16964243 . 10.1038/nbt1240 . vanc . 14294292 .
• Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M . Global, in vivo, and site-specific phosphorylation dynamics in signaling networks . Cell . 127 . 3 . 635–648 . November 2006 . 17081983 . 10.1016/j.cell.2006.09.026 . vanc . 7827573 . free .
• Chandrasekaran R, Thompson M . Polybromo-1-bromodomains bind histone H3 at specific acetyl-lysine positions . Biochemical and Biophysical Research Communications . 355 . 3 . 661–666 . April 2007 . 17320048 . 10.1016/j.bbrc.2007.01.193 .

Notes and References

1. Xue Y, Canman JC, Lee CS, Nie Z, Yang D, Moreno GT, Young MK, Salmon ED, Wang W . 6 . The human SWI/SNF-B chromatin-remodeling complex is related to yeast rsc and localizes at kinetochores of mitotic chromosomes . Proceedings of the National Academy of Sciences of the United States of America . 97 . 24 . 13015–13020 . November 2000 . 11078522 . 27170 . 10.1073/pnas.240208597 . free . 2000PNAS...9713015X .
2. Yu Y, Zhang C, Zhou G, Wu S, Qu X, Wei H, Xing G, Dong C, Zhai Y, Wan J, Ouyang S, Li L, Zhang S, Zhou K, Zhang Y, Wu C, He F . 6 . Gene expression profiling in human fetal liver and identification of tissue- and developmental-stage-specific genes through compiled expression profiles and efficient cloning of full-length cDNAs . Genome Research . 11 . 8 . 1392–1403 . August 2001 . 11483580 . 311073 . 10.1101/gr.175501 .
3. Web site: Entrez Gene: PB1 polybromo 1.
4. Mashtalir N, D'Avino AR, Michel BC, Luo J, Pan J, Otto JE, Zullow HJ, McKenzie ZM, Kubiak RL, St Pierre R, Valencia AM, Poynter SJ, Cassel SH, Ranish JA, Kadoch C . 6 . Modular Organization and Assembly of SWI/SNF Family Chromatin Remodeling Complexes . Cell . 175 . 5 . 1272–1288.e20 . November 2018 . 30343899 . 6791824 . 10.1016/j.cell.2018.09.032 .
5. Web site: Q86U86 : Protein polybromo-1 (Human) . Universal Protein Resource . UniProt Consortium .
6. Shain AH, Pollack JR . The spectrum of SWI/SNF mutations, ubiquitous in human cancers . PLOS ONE . 8 . 1 . e55119 . 2013 . 23355908 . 3552954 . 10.1371/journal.pone.0055119 . free . 2013PLoSO...855119S .
7. 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 . 6 . Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma . Nature . 469 . 7331 . 539–542 . January 2011 . 21248752 . 3030920 . 10.1038/nature09639 . 2011Natur.469..539V .
8. 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 . 6 . Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma . Nature . 469 . 7331 . 539–542 . January 2011 . 21248752 . 3030920 . 10.1038/nature09639 . 2011Natur.469..539V .
9. Gao W, Li W, Xiao T, Liu XS, Kaelin WG . Inactivation of the PBRM1 tumor suppressor gene amplifies the HIF-response in VHL-/- clear cell renal carcinoma . Proceedings of the National Academy of Sciences of the United States of America . 114 . 5 . 1027–1032 . January 2017 . 28082722 . 5293026 . 10.1073/pnas.1619726114 . 2017PNAS..114.1027G . free .
10. Yao X, Hong JH, Nargund AM, Ng MS, Heng HL, Li Z, Guan P, Sugiura M, Chu PL, Wang LC, Ye X, Qu J, Kwek XY, Lim JC, Ooi WF, Koh J, Wang Z, Pan YF, Ong YS, Tan KY, Goh JY, Ng SR, Pignata L, Huang D, Lezhava A, Tay ST, Lee M, Yeo XH, Tam WL, Rha SY, Li S, Guccione E, Futreal A, Tan J, Yeong JP, Hong W, Yauch R, Chang KT, Sobota RM, Tan P, Teh BT . 6 . PBRM1-deficient PBAF complexes target aberrant genomic loci to activate the NF-κB pathway in clear cell renal cell carcinoma . Nature Cell Biology . 25 . 5 . 765–777 . May 2023 . 37095322 . 10.1038/s41556-023-01122-y . 258311941 .
11. Gu YF, Cohn S, Christie A, McKenzie T, Wolff N, Do QN, Madhuranthakam AJ, Pedrosa I, Wang T, Dey A, Busslinger M, Xie XJ, Hammer RE, McKay RM, Kapur P, Brugarolas J . 6 . Modeling Renal Cell Carcinoma in Mice: Bap1 and Pbrm1 Inactivation Drive Tumor Grade . Cancer Discovery . 7 . 8 . 900–917 . August 2017 . 28473526 . 5540776 . 10.1158/2159-8290.CD-17-0292 .
12. Yang Q, Shen R, Xu H, Shi X, Xu L, Zhang L, Fan X, Jin X . 6 . Comprehensive analyses of PBRM1 in multiple cancer types and its association with clinical response to immunotherapy and immune infiltrates . Annals of Translational Medicine . 9 . 6 . 465 . March 2021 . 33850862 . 8039713 . 10.21037/atm-21-289 . free .
13. Carril-Ajuria L, Santos M, Roldán-Romero JM, Rodriguez-Antona C, de Velasco G . Prognostic and Predictive Value of PBRM1 in Clear Cell Renal Cell Carcinoma . Cancers . 12 . 1 . 16 . December 2019 . 31861590 . 7016957 . 10.3390/cancers12010016 . free .