When enough is enough: Detrimental effects of excess histones

Villeneuve, Valérie; Verreault, Alain

doi:10.4161/cc.9.24.14062

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“…The accumulation of nonnucleosomal histones is toxic to cells and leads to DNA replication defects and HU sensitivity (45). We examined the sensitivity of the HBR domain mutants to HU, a drug that blocks DNA replication.…”

Section: The Hbr Domain Is Important For Transcription Activationmentioning

confidence: 99%

A Highly Conserved Region within H2B Is Important for FACT To Act on Nucleosomes

Zheng

Crickard

Srikanth

et al. 2014

Molecular and Cellular Biology

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Histone N-terminal tails play crucial roles in chromatin-related processes. The tails of histones H3 and H4 are highly conserved and well characterized, but much less is known about the functions of the tails of histones H2A and H2B and their sequences are more divergent among eukaryotes. Here we characterized the function of the only highly conserved region in the H2B tail, the H2B repression (HBR) domain. Once thought to play a role only in repression, it also has an uncharacterized function in gene activation and DNA damage responses. We report that deletion of the HBR domain impairs the eviction of nucleosomes at the promoters and open reading frames of genes. A closer examination of the HBR domain mutants revealed that they displayed phenotypes similar to those of histone chaperone complex FACT mutants, including an increase in intragenic transcription and the accumulation of free histones in cells. Biochemical characterization of recombinant nucleosomes indicates that deletion of the HBR domain impairs FACT-dependent removal of H2A-H2B from nucleosomes, suggesting that the HBR domain plays an important role in allowing FACT to disrupt dimer-DNA interactions. We have uncovered a previously unappreciated role for the HBR domain in regulating chromatin structure and have provided insight into how FACT acts on nucleosomes.T he genomes of eukaryotes are packaged into chromatin, which is composed of DNA and the four core histones H2A, H2B, H3, and H4 (1, 2). Each histone contains an N-terminal tail that can be decorated with multiple posttranslational modifications. The modification of residues in the tails controls nuclear functions such as gene expression, mitosis, meiosis, mRNA processing, gene silencing, and DNA repair (2-4). The N-terminal tails of histones H3 and H4 are exceptionally well conserved across all eukaryotes, including the sites of posttranslational modifications. The importance of these tails in regulating chromatin transactions has been interrogated by many studies using the genetically tractable yeast model system. In contrast, the amino acid sequence of the H2A and H2B N-terminal tails are relatively divergent between yeasts and metazoans; thus, much less is known about their functions than about those of H3 and H4.While most of the yeast H2B (yH2B) tail shows minimal sequence similarity to its metazoan counterparts, a short basic region (residues 30 to 37) known as the H2B repression (HBR) domain is highly conserved among all eukaryotes (5, 6). The HBR is located adjacent to the ␣-helical structured region in the H2B tail and passes between the gyres of DNA within the structure of the nucleosome. First it was thought to play a role only in the silencing of telomere-proximal genes, but recent analysis of a mutant containing a deletion of the HBR domain (⌬HBR) revealed that it is important also for DNA damage repair and the activation and repression of genes (7,8). Since the HBR domain residues make contact with DNA, the mutant phenotypes were attributed to weakened histone-DNA interactions....

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Section: The Hbr Domain Is Important For Transcription Activationmentioning

confidence: 99%