Histone H3G34R mutation causes replication stress, homologous recombination defects and genomic instability in S. pombe

Yadav, Rajesh K; Jablonowski, Carolyn M; Fernandez, Alfonso G.; Lowe, Brandon R; Henry, Ryan A.; Finkelstein, David; Barnum, Kevin J; Pidoux, Alison L.; Kuo, Yin-Ming; Huang, Jie; O’Connell, Matthew J.; Andrews, Andrew J.; Onar‐Thomas, Arzu; Allshire, Robin C.; Partridge, Janet F.

doi:10.7554/elife.27406

Cited by 43 publications

(73 citation statements)

References 72 publications

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“…The decrease in K36me1 on the G34V peptide suggests that the mutation inhibits Lys-36 monomethylation.Because Lys-36 methylation antagonizes Lys-27 methylation (61,62), G34V could also promote K27me2 by inhibiting Lys-36 methylation. This result is consistent with reports that the Gly-34 mutations impair Lys-36 methylation (30,35,36). Taken together, these results suggest that the H3.3 Gly-34 mutations dysregulate the post-translational modification of their adjacent Lys-27 and Lys-36 residues.…”

Section: H33(g34v) Dysregulates Lys-27 and Lys-36 Methylation In Cissupporting

confidence: 93%

“…H3.3 glycine 34 is also mutated to either arginine or valine in hemispheric pediatric HGGs and to tryptophan or leucine in giant cell tumor of the bone (GCTB). Less is known about how the Gly-34 mutations promote tumorigenesis, but alterations in H3 Lys-36 methylation have been reported (30,(35)(36)(37). These results suggest that oncohistone H3.3s drive tumorigenesis by dysregulating the chromatin landscape during differentiation.…”

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confidence: 98%

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Rpp29 regulates histone H3.3 chromatin assembly through transcriptional mechanisms

Shastrula

Lund

Garcia

et al. 2018

Journal of Biological Chemistry

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The histone H3 variant H3.3 is a highly conserved and dynamic regulator of chromatin organization. Therefore, fully elucidating its nucleosome incorporation mechanisms is essential to understanding its functions in epigenetic inheritance. We previously identified the RNase P protein subunit, Rpp29, as a repressor of H3.3 chromatin assembly. Here, we use a biochemical assay to show that Rpp29 interacts with H3.3 through a sequence element in its own N terminus, and we identify a novel interaction with histone H2B at an adjacent site. The fact that archaeal Rpp29 does not include this N-terminal region suggests that it evolved to regulate eukaryote-specific functions. Oncogenic H3.3 mutations alter the H3.3-Rpp29 interaction, which suggests that they could dysregulate Rpp29 function in chromatin assembly. We also used KNS42 cells, an H3.3(G34V) pediatric high-grade glioma cell line, to show that Rpp29 1) represses H3.3 incorporation into transcriptionally active protein-coding, rRNA, and tRNA genes; 2) represses mRNA, protein expression, and antisense RNA; and 3) represses euchromatic post-translational modifications (PTMs) and promotes heterochromatic PTM deposition ( histone H3 Lys-9 trimethylation (H3K9me3) and H3.1/2/3K27me3). Notably, we also found that K27me2 is increased and K36me1 decreased on H3.3(G34V), which suggests that Gly-34 mutations dysregulate Lys-27 and Lys-36 methylation in The fact that Rpp29 represses H3.3 chromatin assembly and sense and antisense RNA and promotes H3K9me3 and H3K27me3 suggests that Rpp29 regulates H3.3-mediated epigenetic mechanisms by processing a transcribed signal that recruits H3.3 to its incorporation sites.

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Section: H33(g34v) Dysregulates Lys-27 and Lys-36 Methylation In Cissupporting

confidence: 93%

mentioning

confidence: 98%

Rpp29 regulates histone H3.3 chromatin assembly through transcriptional mechanisms

Shastrula

Lund

Garcia

et al. 2018

Journal of Biological Chemistry

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“…How does this single heterozygous mutation in 15 genes lead to tumorigenesis? In fission yeast that expresses only mutant H3G34R, DNA damage repair by HR is diminished and the DNA repair dynamics at the compromised replication fork are delayed [93]. However, it's known that H3K36me3 controls NHEJ in fission yeast [53].…”

Section: H3k36me3 Associated Ddr In Tumorigenesismentioning

confidence: 99%

H3K36me3, message from chromatin to DNA damage repair

et al. 2020

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Histone marks control many cellular processes including DNA damage repair. This review will focus primarily on the active histone mark H3K36me3 in the regulation of DNA damage repair and the maintenance of genomic stability after DNA damage. There are diverse clues showing H3K36me3 participates in DNA damage response by directly recruiting DNA repair machinery to set the chromatin at a "ready" status, leading to a quick response upon damage. Reduced H3K36me3 is associated with low DNA repair efficiency. This review will also place a main emphasis on the H3K36me3-mediated DNA damage repair in the tumorigenesis of the newly found oncohistone mutant tumors. Gaining an understanding of different aspects of H3K36me3 in DNA damage repair, especially in cancers, would share the knowledge of chromatin and DNA repair to serve to the drug discovery and patient care.

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“…Fission yeast engineered to express only H3G34R exhibit genome instability and is defective for DNA damage repair by homologous recombination and mammalian cells overexpressing H3G34R/V display a hypermutator phenotype . However, unlike H3K27M, H3G34R/V gave no growth advantage to NPCs in culture , nor was introduction of H3G34R and p53 loss into NPCs in the embryonic forebrain able to produce tumours, unlike H3K27M in the same setting .…”

Section: Primary Dominant Mechanisms Of H3g34r/v Oncogenesis Remain Tmentioning

confidence: 99%

Invited Review: Emerging functions of histone H3 mutations in paediatric diffuse high‐grade gliomas

Kasper

Baker

2020

Neuropathology Appl Neurobio

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2020) Neuropathology and Applied Neurobiology 46, 73-85 Emerging functions of histone H3 mutations in paediatric diffuse high-grade gliomas Paediatric diffuse high-grade gliomas (pHGG) are rare, but deadly tumours. The discovery of recurrent mutations in the tail of histone H3, changing lysine 27 to methionine, or glycine 34 to arginine or valine, has illuminated a critical role for epigenetic dysregulation in the aetiology of childhood gliomas and opened new avenues of exploration that have resulted in numerous advances for the field. In this review, we describe the current models of H3K27M mutant cancer that are available to the research community and the insights they have provided on tumour biology and the epigenetic and transcriptional effects of histone mutations. We also review the current understanding of the H3G34R/V mutation and the therapeutic outlook for the treatment of pHGG.

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Histone H3G34R mutation causes replication stress, homologous recombination defects and genomic instability in S. pombe

Cited by 43 publications

References 72 publications

Rpp29 regulates histone H3.3 chromatin assembly through transcriptional mechanisms

Rpp29 regulates histone H3.3 chromatin assembly through transcriptional mechanisms

H3K36me3, message from chromatin to DNA damage repair

Invited Review: Emerging functions of histone H3 mutations in paediatric diffuse high‐grade gliomas

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