title: The double-bromodomain proteins Bdf1 and Bdf2 modulate chromatin structure to regulate S-phase stress response in Schizosaccharomyces pombe.
abstract: Bromodomain proteins bind acetylated histones to regulate transcription. Emerging evidence suggests that histone acetylation plays an important role in DNA replication and repair, although its precise mechanisms are not well understood. Here we report studies of two double bromodomain-containing proteins, Bdf1 and Bdf2, in fission yeast. Loss of Bdf1 or Bdf2 led to a reduction in the level of histone H4 acetylation. Both bdf1Δ and bdf2Δ cells showed sensitivity to DNA damaging agents, including camptothecin, that cause replication fork breakage. Consistently, Bdf1 and Bdf2 were important for recovery of broken replication forks and suppression of DNA damage. Surprisingly, deletion of bdf1 or bdf2 partially suppressed sensitivity of various checkpoint mutants including swi1Δ, mrc1Δ, cds1Δ, crb2Δ, chk1Δ, and rad3Δ, to hydroxyurea, a compound that stalls replication forks and activates the Cds1-dependent S-phase checkpoint. This suppression was not due to reactivation of Cds1. Instead, we found that bdf2 deletion alleviates DNA damage accumulation caused by defects in the DNA replication checkpoint. We also show that hydroxyurea sensitivity of mrc1Δ and swi1Δ was suppressed by mutations in histone H4 acetyltransferase subunits or histone H4. These results suggest that the double bromodomain-containing proteins modulate chromatin structure to coordinate DNA replication and S-phase stress response.
authors.affiliation: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, USA.
authors.forename: Mikael V
authors.initials: MV
authors.lastname: Garabedian
authors.forename: Chiaki
authors.initials: C
authors.lastname: Noguchi
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Ziegler
authors.forename: Mukund M
authors.initials: MM
authors.lastname: Das
authors.forename: Tanu
authors.initials: T
authors.lastname: Singh
authors.forename: Logan J
authors.initials: LJ
authors.lastname: Harper
authors.forename: Adam R
authors.initials: AR
authors.lastname: Leman
authors.forename: Lyne
authors.initials: L
authors.lastname: Khair
authors.forename: Bettina A
authors.initials: BA
authors.lastname: Moser
authors.forename: Toru M
authors.initials: TM
authors.lastname: Nakamura
authors.forename: Eishi
authors.initials: E
authors.lastname: Noguchi
mesh_terms: D000107:Acetylation; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins; D064447:Checkpoint Kinase 2; D002843:Chromatin / Q000737:chemistry*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000235:genetics; D017353:Gene Deletion; D006657:Histones / Q000378:metabolism; D006918:Hydroxyurea / Q000494:pharmacology; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016196:S Phase / Q000235:genetics*; D012568:Schizosaccharomyces / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological / Q000235:genetics*
chemical_list: C572753:Bdf1 protein, S pombe; D018797:Cell Cycle Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D006657:Histones; C533276:MRC1 protein, S pombe; D029702:Schizosaccharomyces pombe Proteins; C513096:swi1 protein, S pombe; D064447:Checkpoint Kinase 2; C578636:Cds1 protein, S pombe; D017346:Protein Serine-Threonine Kinases; D006918:Hydroxyurea
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