title: Histone H2B mono-ubiquitylation maintains genomic integrity at stalled replication forks.
abstract: Histone modifications play an important role in regulating access to DNA for transcription, DNA repair and DNA replication. A central player in these events is the mono-ubiquitylation of histone H2B (H2Bub1), which has been shown to regulate nucleosome dynamics. Previously, it was shown that H2Bub1 was important for nucleosome assembly onto nascent DNA at active replication forks. In the absence of H2Bub1, incomplete chromatin structures resulted in several replication defects. Here, we report new evidence, which shows that loss of H2Bub1 contributes to genomic instability in yeast. Specifically, we demonstrate that H2Bub1-deficient yeast accumulate mutations at a high frequency under conditions of replicative stress. This phenotype is due to an aberrant DNA Damage Tolerance (DDT) response upon fork stalling. We show that H2Bub1 normally functions to promote error-free translesion synthesis (TLS) mediated by DNA polymerase eta (Polη). Without H2Bub1, DNA polymerase zeta (Polζ) is responsible for a highly mutagenic alternative mechanism. While H2Bub1 does not appear to regulate other DDT pathways, error-free DDT mechanisms are employed by H2Bub1-deficient cells as another means for survival. However, in these instances, the anti-recombinase, Srs2, is essential to prevent the accumulation of toxic HR intermediates that arise in an unconstrained chromatin environment.
authors.affiliation: University of Nebraska Medical Center, College of Medicine, Fred and Pamela Buffett Cancer Center, Department of Biochemistry and Molecular Biology, Omaha NE 68198, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Northam
authors.affiliation: University of Nebraska Medical Center, College of Medicine, Fred and Pamela Buffett Cancer Center, Department of Biochemistry and Molecular Biology, Omaha NE 68198, USA kelly.trujillo@unmc.edu.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Trujillo
mesh_terms: D004261:DNA Replication / Q000187:drug effects / Q000528:radiation effects; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D042822:Genomic Instability / Q000187:drug effects / Q000528:radiation effects; D006657:Histones / Q000378:metabolism*; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D050296:Microbial Viability / Q000235:genetics; D009153:Mutagens / Q000494:pharmacology; D009154:Mutation; D059645:Mutation Rate; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011995:Recombination, Genetic; D018741:Replication Origin; D012854:Sister Chromatid Exchange; D013312:Stress, Physiological; D054875:Ubiquitination; D014466:Ultraviolet Rays / Q000009:adverse effects; D015003:Yeasts / Q000235:genetics / Q000378:metabolism
chemical_list: D006657:Histones; D009153:Mutagens; D018809:Proliferating Cell Nuclear Antigen; D008741:Methyl Methanesulfonate; D004259:DNA-Directed DNA Polymerase