A Novel Histone H4 Mutant Defective in Nuclear Division and Mitotic Chromosome Transmission

Smith, M. Mitchell; Yang, Peirong; Santisteban, Maria Soledad; Boone, Paul W.; Goldstein, Alina; Megee, Paul C.

doi:10.1128/mcb.16.3.1017

Cited by 72 publications

(60 citation statements)

References 91 publications

(108 reference statements)

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“…Although many screens for histone mutations that affect genomic stability have been reported (Smith et al 1996;Hyland et al 2005;Matsubara et al 2007;Dai et al 2008;Sakamoto et al 2009;Kawashima et al 2011;Yu et al 2011), none have been specifically directed at measuring chromosome segregation frequencies or sensitivity to Ipl1/Aurora downregulation. While this work was in progress, Kawashima et al (2011) reported a systematic screen of all histone mutants for sensitivity to the microtubule-depolymerizing agents benomyl and thiabendazole.…”

Section: Discussionmentioning

confidence: 99%

Kinetochore Function and Chromosome Segregation Rely on Critical Residues in Histones H3 and H4 in Budding Yeast

Lenstra²,

Duggan

et al. 2013

Genetics

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Accurate chromosome segregation requires that sister kinetochores biorient and attach to microtubules from opposite poles. Kinetochore biorientation relies on the underlying centromeric chromatin, which provides a platform to assemble the kinetochore and to recruit the regulatory factors that ensure the high fidelity of this process. To identify the centromeric chromatin determinants that contribute to chromosome segregation, we performed two complementary unbiased genetic screens using a library of budding yeast mutants in every residue of histone H3 and H4. In one screen, we identified mutants that lead to increased loss of a nonessential chromosome. In the second screen, we isolated mutants whose viability depends on a key regulator of biorientation, the Aurora B protein kinase. Nine mutants were common to both screens and exhibited kinetochore biorientation defects. Four of the mutants map near the unstructured nucleosome entry site, and their genetic interaction with reduced IPL1 can be suppressed by increasing the dosage of SGO1, a key regulator of biorientation. In addition, the composition of purified kinetochores was altered in six of the mutants. Together, this work identifies previously unknown histone residues involved in chromosome segregation and lays the foundation for future studies on the role of the underlying chromatin structure in chromosome segregation.

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Section: Discussionmentioning

confidence: 99%

Kinetochore Function and Chromosome Segregation Rely on Critical Residues in Histones H3 and H4 in Budding Yeast

Lenstra²,

Duggan

et al. 2013

Genetics

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“…Histone H4, the primary acetylation target of NuA4, has also been implicated in chromosome stability (Saunders et al 1990;Meluh et al 1998;Glowczewski et al 2000;Choy et al 2001;Measday et al 2005). While many of these H4 effects are likely to be acetylation-independent (Saunders et al 1990;Smith et al 1996;Glowczewski et al 2000), unacetylatable H4 alleles are sensitive to benomyl (Le Masson et al 2003) and display defects in genome integrity (Megee et al 1995). NuA4 is the only essential HAT in yeast Allard et al 1999), perhaps because it acts in multiple pathways that include transcription and chromosome stability.…”

Section: Htz1-k14mentioning

confidence: 99%

The Saccharomyces cerevisiae histone H2A variant Htz1 is acetylated by NuA4

Keogh¹,

Mennella²,

Sawa³

et al. 2006

Genes Dev.

225

228

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The histone H2A variant H2A.Z (Saccharomyces cerevisiae Htz1) plays roles in transcription, DNA repair, chromosome stability, and limiting telomeric silencing. The Swr1-Complex (SWR-C) inserts Htz1 into chromatin and shares several subunits with the NuA4 histone acetyltransferase. Furthermore, mutants of these two complexes share several phenotypes, suggesting they may work together. Here we show that NuA4 acetylates Htz1 Lys 14 (K14) after the histone is assembled into chromatin by the SWR-C. K14 mutants exhibit specific defects in chromosome transmission without affecting transcription, telomeric silencing, or DNA repair. Functionspecific modifications may help explain how the same component of chromatin can function in diverse pathways. Two classes of enzymes have been implicated in regulating chromatin structure and access to the underlying DNA template. The ATP-dependent chromatin remodeling enzymes use ATP hydrolysis to induce nucleosome mobility or disrupt histone-DNA interactions. The second class of enzymes covalently modify (e.g., lysine acetylation, serine phosphorylation, lysine and arginine methylation, ubiquitylation, or ADP ribosylation) various histones, usually on their N-terminal tails (Strahl and Allis 2000; Jenuwein and Allis 2001). Acetylation is carried out by histone acetyltransferases (HATs), which in Saccharomyces cerevisiae include the Gcn5-containing ADA and SAGA complexes, Hat1, Elongator, NuA3, and NuA4 (for review, see Bottomley 2004). These typically have specificity for distinct lysine residues on certain histone N-terminal tails. The acetylation of lysine residues on the N-terminal tails of histones H3 and H4 neutralizes their positive charge, possibly decreasing their affinity for DNA and facilitating chromatin decompaction and disassembly (Eberharter and Becker 2002). Perhaps more important than simple charge neutralization is the specific pattern of acetylation at individual lysine residues, at least some of which recruit bromodomain-containing proteins (Matangkasombut and Buratowski 2003, and references therein).Further chromatin specialization can be introduced by incorporation of variant histones. The major histones are assembled during DNA replication, but can be replaced by variants at specific locations (for review, see The SWR-C shares several subunits with the NuA4 HAT complex (Kobor et al. 2004;Krogan et al. 2004;Mizuguchi et al. 2004), and expression microarray analysis shows the two complexes have common regulatory targets (Krogan et al. 2004). NuA4 is required for the majority of histone H4 acetylation on Lys 5 (K5), K8, and K12 and some on histone H2A K7 Allard et al. 1999). Htz1, SWR-C, and NuA4 have each been implicated in the maintenance of chromosome stability (Krogan et al. 2004). This function for H2A.Z is conserved in the fission yeast Schizosaccharomyces pombe (Carr et al. 1994) and metazoans (Rangasamy et al. 2004).How NuA4 and SWR-C are functionally connected remains unclear. Htz1 incorporation into chromatin is dependent on SWR-C, but independent of NuA...

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“…After incubation for 2 h on ice, the soluble chromatin fraction was obtained by centrifugation. Purification of core histones from isolated yeast nuclei was performed according to the method of Smith et al (1996).…”

Section: Preparation Of Nuclei Chromatin Fraction and Core Histonesmentioning

confidence: 99%

The Nuclear Actin-related Protein ofSaccharomyces cerevisiae, Act3p/Arp4, Interacts with Core Histones

Harata

Oma

Mizuno

et al. 1999

MBoC

119

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Act3p/Arp4, an essential actin-related protein of Saccharomyces cerevisiae located within the nucleus, is, according to genetic data, involved in transcriptional regulation. In addition to the basal core structure of the actin family members, which is responsible for ATPase activity, Act3p possesses two insertions, insertions I and II, the latter of which is predicted to form a loop-like structure protruding from beyond the surface of the molecule. Because Act3p is a constituent of chromatin but itself does not bind to DNA, we hypothesized that insertion II might be responsible for an Act3p-specific function through its interaction with some other chromatin protein. Far Western blot and two-hybrid analyses revealed the ability of insertion II to bind to each of the core histones, although with somewhat different affinities. Together with our finding of coimmunoprecipitation of Act3p with histone H2A, this suggests the in vivo existence of a protein complex required for correct expression of particular genes. We also show that a conditional act3 mutation affects chromatin structure of an episomal DNA molecule, indicating that the putative Act3p complex may be involved in the establishment, remodeling, or maintenance of chromatin structures.

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A Novel Histone H4 Mutant Defective in Nuclear Division and Mitotic Chromosome Transmission

Cited by 72 publications

References 91 publications

Kinetochore Function and Chromosome Segregation Rely on Critical Residues in Histones H3 and H4 in Budding Yeast

Kinetochore Function and Chromosome Segregation Rely on Critical Residues in Histones H3 and H4 in Budding Yeast

The Saccharomyces cerevisiae histone H2A variant Htz1 is acetylated by NuA4

The Nuclear Actin-related Protein ofSaccharomyces cerevisiae, Act3p/Arp4, Interacts with Core Histones

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