Alternative titles; symbols
HGNC Approved Gene Symbol: PBRM1
SNOMEDCT: 1187306007, 254915003, 41607009;
Cytogenetic location: 3p21.1 Genomic coordinates (GRCh38) : 3:52,545,367-52,685,913 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p21.1 | ?Renal cell carcinoma, clear cell | 144700 | 3 |
The PBRM1 gene encodes the BAF180 protein, the chromatin targeting subunit of the PBAF SWI/SNF chromatin remodeling complex (summary by Varela et al., 2011).
Multisubunit ATP-dependent chromatin-remodeling complexes facilitate the opening of chromatin structures to allow transcription and other metabolic reactions to occur on DNA. The complexes contain an ATPase related to yeast Swi2/Snf2-like ATPases (e.g., SMARCA2; 600014) and use the energy of ATP hydrolysis to disrupt nucleosomes. By biochemical purification of the Polybromo- and BRG1 (603254)-associated factor (PBAF) complex, or SWI/SNF complex B, followed by micropeptide sequence analysis, EST database searching, and screening of a T-cell cDNA library, Xue et al. (2000) obtained a cDNA encoding BAF180. Immunoblot analysis showed that BAF180 was expressed as a 180-kD protein. The deduced 1,582-amino acid BAF180 protein, which is 90% identical to the chicken polybromo-1 protein, possesses 5 bromodomains, 2 bromo-adjacent homology (BAH) regions, and 1 high-mobility group (HMG) motif. BAF180 is also highly homologous to yeast Rsc1, Rsc2, and Rsc3, essential proteins that are required for cell cycle progression through mitosis. Northern blot analysis revealed wide expression of 9.5- and 7.5-kb BAF180 transcripts. Immunofluorescence microscopy demonstrated that BAF180 was expressed in the nucleus during interphase but colocalized with cytoplasmic dynein (see 600112) at some kinetochores during prometaphase. The localization of BAF180 at kinetochores was not observed in metaphase, anaphase, or telophase. Xue et al. (2000) proposed that BAF180 and PBAF are more closely related to yeast Rsc than to SWI/SNF.
Varela et al. (2011) stated that the PBRM1 gene maps to chromosome 3p21.
Using an integrated chromatin-dependent reconstituted transcription reaction, Lemon et al. (2001) identified PBAF, but not SWI/SNF or the ISWI (see 603375)-containing chromatin remodeling complex ACF, as a cofactor necessary for ligand-dependent transactivation by nuclear hormone receptors. Further immunoprecipitation analysis determined that PBAF as well as TFIID (see 313650) and ARC (see 605718) are required for transcription from a chromatin template, but only TFIID is needed for transcription from naked DNA. Lemon et al. (2001) suggested that different chromatin-remodeling complexes may perform quite specific functions that are not interchangeable in supporting transcription.
Using a genome-scale CRISPR-Cas9 screen, Pan et al. (2018) identified mechanisms of tumor cell resistance to killing by cytotoxic T cells, the central effectors of antitumor immunity. Inactivation of more than 100 genes, including Pbrm1, Arid2 (609539), and Brd7 (618489), which encode components of the PBAF form of the SWI/SNF chromatin remodeling complex, sensitized mouse B16F10 melanoma cells to killing by T cells. Loss of PBAF function increased tumor cell sensitivity to interferon-gamma (147570), resulting in enhanced secretion of chemokines that recruit effector T cells. Treatment-resistant tumors became responsive to immunotherapy when Pbrm1 was inactivated. In many human cancers, expression of PBRM1 and ARID2 inversely correlated with expression of T cell cytotoxicity genes, and Pbrm1-deficient murine melanomas were more strongly infiltrated by cytotoxic T cells.
To identify genomic alterations in clear-cell renal cell carcinoma that correlate with response to anti-PD1 (600244) monotherapy, Miao et al. (2018) performed whole-exome sequencing of metastatic clear-cell renal cell carcinoma from 35 patients and found that clinical benefit was associated with loss-of-function mutations in the PBRM1 gene (p = 0.012), which encodes a subunit of the PBAF switch-sucrose nonfermentable (SWI/SNF) chromatin remodeling complex. Miao et al. (2018) confirmed this finding in an independent validation cohort of 63 clear-cell renal cell carcinoma patients treated with PD1 or PDL1 (605402) blockade therapy alone or in combination with anti-CTLA4 (123890) therapies (p = 0.0071). Gene expression analysis of PBAF-deficient clear-cell renal cell carcinoma cell lines and PBRM1-deficient tumors revealed altered transcriptional output in JAK-STAT hypoxia, and immune signaling pathways.
Varela et al. (2011) sequenced the protein coding exome in a series of primary clear cell renal cell carcinoma (ccRCC) and reported the identification of mutations in PBRM1 as a second (VHL, 608537 being the first) major ccRCC cancer gene, with truncating mutations in 41% (92/227) of cases. Varela et al. (2011) concluded that their data further elucidated the somatic genetic architecture of ccRCC and emphasized the marked contribution of aberrant chromatin biology.
Benusiglio et al. (2015) reported a 3-generation family in which heterozygous mutation in the PBRM1 gene (606083.0001) segregated with clear cell renal cell carcinoma.
Wang et al. (2004) found that Baf180-null mouse embryos died between embryonic day 12.5 and 15.5. Most organs were present and appeared grossly normal, except that liver and lung were small. Mutant embryos showed generalized edema due to reduced heart rate and blood volume. Histologic examination revealed severe hypoplasia of the cardiac ventricular free walls, as well as ventricular septal defect; other heart structures appeared normal. Tunnel assays indicated a failure in cell growth or differentiation rather than cell death caused the heart defects. Placentas from Baf180-null fetuses were also abnormal, with indistinct spongiotrophoblast and labyrinthine layers. Wang et al. (2004) found that Baf180 was recruited to the promoter regions of S100a13 (601989), Rarb2 (RARB; 180220), and Crabp2 (180231), and Baf180 deficiency affected the retinoic acid responses of Rarb2 and Crabp2.
In a family with clear cell renal cell carcinoma (ccRCC; 144700) in 3 generations, Benusiglio et al. (2015) identified a heterozygous germline mutation in PBRM1, an 8-bp deletion (c.3998_4005del, ENST00000296302) in exon 24 that resulted in an asp-to-gly substitution at codon 1333 with a frameshift 3 amino acids downstream (Asp1333Glyfs). Neither this mutation nor any PBRM1 truncating mutation was reported in 6,503 Caucasian and African American individuals in the NHLBI Exome Sequencing Project Exome Variant Server. The mutation segregated with the disease in the family that included the proband, who was diagnosed at age 38; his older sister, diagnosed at age 42; that sister's daughter, diagnosed at age 36; and the mother of the proband, who was diagnosed at ages 64 and 70 with clear cell renal cell carcinoma.
Benusiglio, P. R., Couve, S., Gilbert-Dussardier, B., Deveaux, S., Le Jeune, H., Da Costa, M., Fromont, G., Memeteau, F., Yacoub, M., Coupier, I., Leroux, D., Mejean, A., and 8 others. A germline mutation in PBRM1 predisposes to renal cell carcinoma. J. Med. Genet. 52: 426-430, 2015. [PubMed: 25911086] [Full Text: https://doi.org/10.1136/jmedgenet-2014-102912]
Lemon, B., Inouye, C., King, D. S., Tjian, R. Selectivity of chromatin-remodeling cofactors for ligand-activated transcription. Nature 414: 924-928, 2001. [PubMed: 11780067] [Full Text: https://doi.org/10.1038/414924a]
Miao, D., Margolis, C. A., Gao, W., Voss, M. H., Li, W., Martini, D. J., Norton, C., Bosse, D., Wankowicz, S. M., Cullen, D., Horak, C., Wind-Rotolo, M., and 14 others. Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science 359: 801-806, 2018. [PubMed: 29301960] [Full Text: https://doi.org/10.1126/science.aan5951]
Pan, D., Kobayashi, A., Jiang, P., Ferrari de Andrade, L., Tay, R. E., Luoma, A. M., Tsoucas, D., Qiu, X., Lim, K., Rao, P., Long, H. W., Yuan, G.-C., Doench, J., Brown, M., Liu, X. S., Wucherpfennig, K. W. A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing. Science 359: 770-775, 2018. [PubMed: 29301958] [Full Text: https://doi.org/10.1126/science.aao1710]
Varela, I., Tarpey, P., Raine, K., Huang, D., Ong, C. K., Stephens, P., Davies, H., Jones, D., Lin, M.-L., Teague, J., Bignell, G., Butler, A., and 32 others. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 469: 539-542, 2011. Note: Erratum: Nature 484: 130 only, 2012. [PubMed: 21248752] [Full Text: https://doi.org/10.1038/nature09639]
Wang, Z., Zhai, W., Richardson, J. A., Olson, E. N., Meneses, J. J., Firpo, M. T., Kang, C., Skarnes, W. C., Tjian, R. Polybromo protein BAF180 functions in mammalian cardiac chamber maturation. Genes Dev. 18: 3106-3116, 2004. [PubMed: 15601824] [Full Text: https://doi.org/10.1101/gad.1238104]
Xue, Y., Canman, J. C., Lee, C. S., Nie, Z., Yang, D., Moreno, G. T., Young, M. K., Salmon, E. D., Wang, W. The human SW1/SNF-B chromatin-remodeling complex is related to yeast Rsc and localizes at kinetochores of mitotic chromosomes. Proc. Nat. Acad. Sci. 97: 13015-13020, 2000. [PubMed: 11078522] [Full Text: https://doi.org/10.1073/pnas.240208597]