title: BAF180 promotes cohesion and prevents genome instability and aneuploidy.
abstract: BAF180, a subunit of the PBAF chromatin remodeling complex, is frequently mutated in cancer. Although PBAF regulates transcription, it remains unclear whether this is what drives tumorigenesis in cells lacking BAF180. Based on data from yeast, we hypothesized that BAF180 may prevent tumorigenesis by promoting cohesion. Here, we show BAF180 is required for centromeric cohesion in mouse and human cells. Mutations identified in tumor samples are unable to support this activity, and also compromise cohesion-dependent functions in yeast. We provide evidence of genome instability in line with loss of cohesion, and importantly, we find dynamic chromosome instability following DNA damage in cells lacking BAF180. These data demonstrate a function for BAF180 in promoting genome stability that is distinct from its well-characterized role in transcriptional regulation, uncovering a potent mechanism for its tumor-suppressor activity.
authors.affiliation: MRC Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton BN1 9RQ, UK.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Brownlee
authors.affiliation: MRC Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton BN1 9RQ, UK.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Chambers
authors.affiliation: MRC Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton BN1 9RQ, UK.
authors.forename: Ross
authors.initials: R
authors.lastname: Cloney
authors.affiliation: MRC Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton BN1 9RQ, UK.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bianchi
authors.affiliation: MRC Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton BN1 9RQ, UK. Electronic address: j.a.downs@sussex.ac.uk.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Downs
mesh_terms: D000782:Aneuploidy; D000818:Animals; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D042822:Genomic Instability; D024002:HMGB Proteins / Q000235:genetics*; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D024002:HMGB Proteins; D009687:Nuclear Proteins; C102195:PBRM1 protein, human; C496872:Pbrm1 protein, mouse; D014157:Transcription Factors