title: Requirement for PBAF in transcriptional repression and repair at DNA breaks in actively transcribed regions of chromatin.
abstract: Actively transcribed regions of the genome are vulnerable to genomic instability. Recently, it was discovered that transcription is repressed in response to neighboring DNA double-strand breaks (DSBs). It is not known whether a failure to silence transcription flanking DSBs has any impact on DNA repair efficiency or whether chromatin remodelers contribute to the process. Here, we show that the PBAF remodeling complex is important for DSB-induced transcriptional silencing and promotes repair of a subset of DNA DSBs at early time points, which can be rescued by inhibiting transcription globally. An ATM phosphorylation site on BAF180, a PBAF subunit, is required for both processes. Furthermore, we find that subunits of the PRC1 and PRC2 polycomb group complexes are similarly required for DSB-induced silencing and promoting repair. Cancer-associated BAF180 mutants are unable to restore these functions, suggesting PBAF's role in repressing transcription near DSBs may contribute to its tumor suppressor activity.
authors: MRC Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton BN1 9RQ, UK.
authors: Andreas
authors: A
authors: Kakarougkas
authors: MRC Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton BN1 9RQ, UK.
authors: Amani
authors: A
authors: Ismail
authors: MRC Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton BN1 9RQ, UK.
authors: Anna L
authors: AL
authors: Chambers
authors: MRC Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton BN1 9RQ, UK.
authors: Enriqueta
authors: E
authors: Riballo
authors: MRC Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton BN1 9RQ, UK.
authors: Alex D
authors: AD
authors: Herbert
authors: Radiation Biology and DNA Repair, Darmstadt University of Technology, 64287 Darmstadt, Germany.
authors: Julia
authors: J
authors: Künzel
authors: Radiation Biology and DNA Repair, Darmstadt University of Technology, 64287 Darmstadt, Germany.
authors: Markus
authors: M
authors: Löbrich
authors: MRC Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton BN1 9RQ, UK. Electronic address: p.a.jeggo@sussex.ac.uk.
authors: Penny A
authors: PA
authors: Jeggo
authors: MRC Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton BN1 9RQ, UK. Electronic address: j.a.downs@sussex.ac.uk.
authors: Jessica A
authors: JA
authors: Downs
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism / Q000502:physiology*; D053960:DNA Breaks; D059766:DNA End-Joining Repair; D004260:DNA Repair; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D054875:Ubiquitination
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D006657:Histones; D009687:Nuclear Proteins; C102195:PBRM1 protein, human; C445179:SWI-SNF-B chromatin-remodeling complex; D014157:Transcription Factors