Genetic interactions between POB3 and the acetylation of newly synthesized histones

Nair, Devi M.; Ge, Zhongqi; Mersfelder, Erica L.; Parthun, Mark R.

doi:10.1007/s00294-011-0347-1

Cited by 8 publications

(7 citation statements)

References 69 publications

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“…6C). This physical interaction was consistent with the recently reported genetic interactions that suggest a role for the yFACT complex in guiding newly synthesized histones into chromatin (29). The unique H3K56ac specificity of Rtt106 suggested that the modification-independent recognition surface would be functionally conserved between Pob3 and Rtt106, whereas the H3K56ac-specific recognition surface would be important only for Rtt106-histone binding.…”

Section: Rtt106:h3 Binding Was Required For the Delivery Of H3k56ac Dsupporting

confidence: 89%

“…6A). Rtt106 and Pob3 both interact with histones H3/H4, and a mutant allele of pob3 interacts genetically with mutations on H3 at K56 (7,29). Therefore, we determined whether the histone-binding mechanism and acetyl-lysine specificity were conserved between these structurally similar chromatin-associated proteins.…”

Section: Rtt106:h3 Binding Was Required For the Delivery Of H3k56ac Dmentioning

confidence: 99%

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Two surfaces on the histone chaperone Rtt106 mediate histone binding, replication, and silencing

Zunder

Antczak

Berger

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The histone chaperone Rtt106 binds histone H3 acetylated at lysine 56 (H3K56ac) and facilitates nucleosome assembly during several molecular processes. Both the structural basis of this modificationspecific recognition and how this recognition informs Rtt106 function are presently unclear. Guided by our crystal structure of Rtt106, we identified two regions on its double-pleckstrin homology domain architecture that mediated histone binding. When histone binding was compromised, Rtt106 localized properly to chromatin but failed to deliver H3K56ac, leading to replication and silencing defects. By mutating analogous regions in the structurally homologous chromatin-reorganizer Pob3, we revealed a conserved histone-binding function for a basic patch found on both proteins. In contrast, a loop connecting two β-strands was required for histone binding by Rtt106 but was dispensable for Pob3 function. Unlike Rtt106, Pob3 histone binding was modification-independent, implicating the loop of Rtt106 in H3K56ac-specific recognition in vivo. Our studies described the structural origins of Rtt106 function, identified a conserved histone-binding surface, and defined a critical role for Rtt106:H3K56ac-binding specificity in silencing and replication-coupled nucleosome turnover.histone acetylation | yFACT | CAF-1 | Sir | Saccharomyces cerevisiae

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Section: Rtt106:h3 Binding Was Required For the Delivery Of H3k56ac Dsupporting

confidence: 89%

Section: Rtt106:h3 Binding Was Required For the Delivery Of H3k56ac Dmentioning

confidence: 99%

Two surfaces on the histone chaperone Rtt106 mediate histone binding, replication, and silencing

Zunder

Antczak

Berger

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…These results were confirmed by confocal immunofluorescence analyses in which a uniform increase in γH2AX was observed 6 h after NCS treatment in SUPT16H-knockdown cells in yeast. 35 Furthermore, H2Bub1 was shown to cooperate with FACT during transcriptional elongation, 23 whereby it was proposed that FACT catalyzes an exchange of histone H2A-H2B dimers in an H2Bub1-dependent manner. 36 Based on the effects of RNF40 knockdown on H3K56ac, we hypothesized that a loss of H2Bub1 may lead to impaired histone exchange following DNA damage through decreased FACT recruitment.…”

Section: Resultsmentioning

confidence: 99%

The H2B ubiquitin ligase RNF40 cooperates with SUPT16H to induce dynamic changes in chromatin structure during DNA double-strand break repair

Kari¹,

Shchebet²,

Neumann³

et al. 2011

Cell Cycle

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Many anticancer therapies function largely by inducing DNA double-strand breaks (DSBs) or altering the ability of cancer cells to repair them. Proper and timely DNA repair requires dynamic changes in chromatin assembly and disassembly characterized by histone H3 lysine 56 acetylation (H3K56ac) and phosphorylation of the variant histone H2AX (γH2AX). Similarly, histone H2B monoubiquitination (H2Bub1) functions in DNA repair, but its role in controlling dynamic changes in chromatin structure following DSBs and the histone chaperone complexes involved remain unknown. Therefore, we investigated the role of the H2B ubiquitin ligase RNF40 in the DSB response. We show that RNF40 depletion results in sustained H2AX phosphorylation and a decrease in rapid cell cycle checkpoint activation. Furthermore, RNF40 knockdown resulted in decreased H3K56ac and decreased recruitment of the facilitates chromatin transcription (FACT) complex to chromatin following DSB. Knockdown of the FACT component suppressor of Ty homolog-16 (SUPT16H) phenocopied the effects of RNF40 knockdown on both γH2AX and H3K56ac following DSB induction. Consistently, both RNF40 and SUPT16H were required for proper DNA end resection and timely DNA repair, suggesting that H2Bub1 and FACT cooperate to increase chromatin dynamics, which facilitates proper checkpoint activation and timely DNA repair. These results provide important mechanistic insights into the tumor suppressor function of H2Bub1 and provide a rational basis for pursuing H2Bub1-based therapies in conjunction with traditional chemo- and radiotherapy.

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“…Initial genetic studies in yeast using mutations that altered H4 lysines 5 and 12 to arginine indicated that the absence of this modification was well tolerated (30,31,66,67). More-recent studies have shown that the H4 K5,12R allele can have a significant effect on cell viability in strain backgrounds that have mutations in the Pob3p subunit of the yeast FACT (facilitates chromatin transcription) complex (28,68). These studies suggest that FACT may be involved in nucleosome assembly but, given the multifunctional nature of the FACT complex, do not shed light on the specific function of H4 lysine 5/12 acetylation.…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in yeast that alter H4 lysine 91 cause severe defects in silent chromatin formation and sensitivity to DNA-damaging agents. Consistent with a role for H4 lysine 91 acetylation in chromatin assembly, genetic analysis of these mutations indicates that this modification functions in common pathways with the histone chaperones Asf1 and CAF-1 in the context of DNA repair (23,28). A histone acetyltransferase, termed HAT4, that appears to be responsible for this modification was recently isolated from mammalian cells.…”

mentioning

confidence: 99%

Sites of Acetylation on Newly Synthesized Histone H4 Are Required for Chromatin Assembly and DNA Damage Response Signaling

Nair

Guan

et al. 2013

Molecular and Cellular Biology

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The best-characterized acetylation of newly synthesized histone H4 is the diacetylation of the NH 2 -terminal tail on lysines 5 and 12. Despite its evolutionary conservation, this pattern of modification has not been shown to be essential for either viability or chromatin assembly in any model organism. We demonstrate that mutations in histone H4 lysines 5 and 12 in yeast confer hypersensitivity to replication stress and DNA-damaging agents when combined with mutations in histone H4 lysine 91, which has also been found to be a site of acetylation on soluble histone H4. In addition, these mutations confer a dramatic decrease in cell viability when combined with mutations in histone H3 lysine 56. We also show that mutation of the sites of acetylation on newly synthesized histone H4 results in defects in the reassembly of chromatin structure that accompanies the repair of HO-mediated double-strand breaks. This defect is not due to a decrease in the level of histone H3 lysine 56 acetylation. Intriguingly, mutations that alter the sites of newly synthesized histone H4 acetylation display a marked decrease in levels of phosphorylated H2A (␥-H2AX) in chromatin surrounding the double-strand break. These results indicate that the sites of acetylation on newly synthesized histones H3 and H4 can function in nonoverlapping ways that are required for chromatin assembly, viability, and DNA damage response signaling. Each time a eukaryotic cell divides, it must duplicate not only its genomic DNA but also the chromatin structure in which it is packaged. At its most fundamental level, chromatin structure consists of ϳ147 bp of DNA wrapped around the histone octamer (which contains two molecules of each of the core histones, H2A, H2B, H3, and H4) to form a nucleosome. The linear strings of nucleosomes that package eukaryotic chromosomes can then form a number of successively higher-order structures to achieve the necessary level of compaction. The rapid and efficient regeneration of chromatin structure during DNA synthesis is essential for the mechanical packaging of the enormous linear length of eukaryotic chromosomes within the confines of the nucleus as well as for the physical protection of the DNA that ensures genomic integrity. Importantly, as posttranslational modifications to histones are an integral component of epigenetic regulation, the process of chromatin assembly also plays a critical role in the inheritance of distinct chromatin states.

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Genetic interactions between POB3 and the acetylation of newly synthesized histones

Cited by 8 publications

References 69 publications

Two surfaces on the histone chaperone Rtt106 mediate histone binding, replication, and silencing

Two surfaces on the histone chaperone Rtt106 mediate histone binding, replication, and silencing

The H2B ubiquitin ligase RNF40 cooperates with SUPT16H to induce dynamic changes in chromatin structure during DNA double-strand break repair

Sites of Acetylation on Newly Synthesized Histone H4 Are Required for Chromatin Assembly and DNA Damage Response Signaling

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