The role of histone H3K36me3 writers, readers and erasers in maintaining genome stability

Sharda, Asmita; Humphrey, Timothy C.

doi:10.1016/j.dnarep.2022.103407

Cited by 25 publications

(20 citation statements)

References 165 publications

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“…Generally, DNA damage could cause cell cycle arrest. The abundance of H3K36me3 ensures the recruitment of DNA damage repair key proteins during DNA replication to restore genome integrity in G1 and early S phase ( 40 , 104 ). Replication fork speed is also decreased in ccRCC cells when SETD2 is depleted ( 35 ).…”

Section: Setd2 and Clear Cell Renal Cell Carcinomasmentioning

confidence: 99%

Histone methyltransferase SETD2: An epigenetic driver in clear cell renal cell carcinoma

Qian

Wang

et al. 2023

Front. Oncol.

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SET domain-containing 2 (SETD2) is a lysine methyltransferase that catalyzes histone H3 lysine36 trimethylation (H3K36me3) and has been revealed to play important roles in the regulation of transcriptional elongation, RNA splicing, and DNA damage repair. SETD2 mutations have been documented in several cancers, including clear cell renal cell carcinoma (ccRCC). SETD2 deficiency is associated with cancer occurrence and progression by regulating autophagy flux, general metabolic activity, and replication fork speed. Therefore, SETD2 is considered a potential epigenetic therapeutic target and is the subject of ongoing research on cancer-related diagnosis and treatment. This review presents an overview of the molecular functions of SETD2 in H3K36me3 regulation and its relationship with ccRCC, providing a theoretical basis for subsequent antitumor therapy based on SETD2 or H3K36me3 targets.

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Section: Setd2 and Clear Cell Renal Cell Carcinomasmentioning

confidence: 99%

Histone methyltransferase SETD2: An epigenetic driver in clear cell renal cell carcinoma

Qian

Wang

et al. 2023

Front. Oncol.

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“…SETD2 is a methyltransferase responsible for the tri-methylation of lysine 36 on histone H3 (H3K36me3). SETD2 and this epigenetic mark regulate transcriptional fidelity, RNA splicing, and the DNA damage response 10 . SETD2 is also widely recognized as a tumor suppressor that is frequently mutated or deleted in many tumor types, including clear cell renal cell carcinoma (ccRCC), pediatric acute lymphoblastic leukemia, lung, bladder, and uterine cancer 11 .…”

Section: Mainmentioning

confidence: 99%

SETD2 safeguards the genome against isochromosome formation

Mason

Kounlavong

Tebeje

et al. 2022

Preprint

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Factors governing the faithful replication of chromosomes are essential for cellular and genomic integrity. While a variety of mechanisms to manage breaks and promote repair of DNA are widely recognized, epigenetic landmarks that preserve telomere-to-telomere replication fidelity and prevent genome instability are not well-understood. SETD2 is the histone methyltransferase responsible for trimethylation on histone H3 lysine 36 and is newly recognized as a tumor suppressor that acts to maintain genome stability. Importantly, SETD2 is frequently lost in cancers that exhibit extensive intratumoral heterogeneity. Here, we demonstrate that loss of SETD2 and H3K36me3 promotes chromosome segregation errors and DNA bridging during mitosis, and that these bridges are driven by the formation of dicentric chromosomes. Cytogenetic analyses revealed that these chromosomes were comprised of mirror-imaged isochromosomes and isodicentric chromosomes that contain two active centromeres. These data demonstrate that the SETD2 histone methyltransferase is essential to prevent a palindromic replication intermediate, whose loss precipitates the formation of a mutable chromatin structure known to initiate a cascade of genomic instability in cancer.

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“…SETD2 is a crucial methyltransferase conserved from yeast to man, methylating substrates such as histone H3 ( Edmunds et al, 2008 ), tubulin ( Andrieux and Sadoul, 2021 ), and signal transducer and activator of transcription 1 (STAT1) ( Chen et al, 2017 ). SETD2 is non-redundantly responsible for all trimethylation of lysine 36 of histone H3 and physically interacts with Pol II and various hnRNPs, which plays an important role in epigenetic modification, regulation of transcription, DNA replication and DNA damage repair ( Edmunds et al, 2008 ; Bhattacharya et al, 2021 ; Molenaar and van Leeuwen, 2022 ; Sharda and Humphrey, 2022 ). Dysregulation of SETD2 function has also been reported in a series of neurological disorders and cancers including ID/DD ( Faundes et al, 2018 ), autism/ASD ( D'Gama et al, 2015 ), renal clear cell carcinoma ( Rao et al, 2021 ) and acute lymphocytic leukemia ( Mar et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

A novel SETD2 variant causing global development delay without overgrowth in a Chinese 3-year-old boy

Liu

Wan

et al. 2023

Front. Genet.

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Background: Luscan-Lumish syndrome is characterized by macrocephaly, postnatal overgrowth, intellectual disability (ID), developmental delay (DD), which is caused by heterozygous SETD2 (SET domain containing 2) mutations. The incidence of Luscan-Lumish syndrome is unclear. The study was conducted to provide a novel pathogenic SETD2 variant causing atypical Luscan-Lumish syndrome and review all the published SETD2 mutations and corresponding symptoms, comprehensively understanding the phenotypes and genotypes of SETD2 mutations.Methods: Peripheral blood samples of the proband and his parents were collected for next-generation sequencing including whole-exome sequencing (WES), copy number variation (CNV) detection and mitochondrial DNA sequencing. Identified variant was verified by Sanger sequencing. Conservative analysis and structural analysis were performed to investigate the effect of mutation. Public databases such as PubMed, Clinvar and Human Gene Mutation Database (HGMD) were used to collect all cases with SETD2 mutations.Results: A novel pathogenic SETD2 variant (c.5835_c.5836insAGAA, p. A1946Rfs*2) was identified in a Chinese 3-year-old boy, who had speech and motor delay without overgrowth. Conservative analysis and structural analysis showed that the novel pathogenic variant would loss the conserved domains in the C-terminal region and result in loss of function of SETD2 protein. Frameshift mutations and non-sense mutations account for 68.5% of the total 51 SETD2 point mutations, suggesting that Luscan-Lumish syndrome is likely due to loss of function of SETD2. But we failed to find an association between genotype and phenotype of SETD2 mutations.Conclusion: Our findings expand the genotype-phenotype knowledge of SETD2-associated neurological disorder and provide new evidence for further genetic counselling.

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The role of histone H3K36me3 writers, readers and erasers in maintaining genome stability

Cited by 25 publications

References 165 publications

Histone methyltransferase SETD2: An epigenetic driver in clear cell renal cell carcinoma

Histone methyltransferase SETD2: An epigenetic driver in clear cell renal cell carcinoma

SETD2 safeguards the genome against isochromosome formation

A novel SETD2 variant causing global development delay without overgrowth in a Chinese 3-year-old boy

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