SETD2-Dependent Histone H3K36 Trimethylation Is Required for Homologous Recombination Repair and Genome Stability

Pfister, Sophia X.; Ahrabi, Sara; Zalmas, Lykourgos-Panagiotis; Sarkar, Sovan; Aymard, François; Bachrati, Csanád Z.; Helleday, Thomas; Legube, Gaëlle; Thangué, Nicholas B. La; Porter, Andrew C.G.; Humphrey, Timothy C.

doi:10.1016/j.celrep.2014.05.026

Cited by 396 publications

(414 citation statements)

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“…Indeed, we showed that depletion of the main H3K36me3 histone methyltransferase, SETD2, 18 is necessary for HR repair of "HR-prone" DSBs. 22 Concomitantly, 2 other groups reported the critical function of human SETD2 in homologous recombination 23,24 using other experimental systems such as I-SceIand radiation-induced DSBs. Furthermore, SETD2 depletion seemed to favor repair by MMEJ.…”

Section: Function Of H3k36me3 In Dsb Repair Pathway Choicementioning

confidence: 99%

DNA double strand break repair pathway choice: a chromatin based decision?

Clouaire

Legube

2015

Nucleus

100

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Section: Function Of H3k36me3 In Dsb Repair Pathway Choicementioning

confidence: 99%

DNA double strand break repair pathway choice: a chromatin based decision?

Clouaire

Legube

2015

Nucleus

100

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“…Several recent studies have examined the effect of SETD2 loss in human cells on the response to DNA damage (22)(23)(24)(25)(26). To further explore the role of H3K36me3 in the DNA damage response, we irradiated HKC to 2 Gy and then performed immunofluorescence for ␥H2A.X, a marker of DNA damage.…”

Section: Setd2/set2 Domain Mutations and H3k36 Methylationmentioning

confidence: 99%

“…In yeast, Set2 mediates all H3K36 methylation states (H3K36me1/me2/ me3) (17) and regulates the recruitment of chromatin-remodeling enzymes (Isw1b) and a histone deacetylase (Rpd3) (18) that functions to keep gene bodies deacetylated, thereby maintaining a more compact chromatin structure (19,20) that is more resistant to inappropriate and bidirectional transcription (18,21). The Set2/SETD2 pathway is also important for DNA repair (22)(23)(24)(25)(26)(27) in both yeast and humans, as well as for proper mRNA splicing (12,28,29). Although yeast Set2 can mediate all forms of H3K36 methylation, SETD2 only trimethylates H3K36 (13).…”

mentioning

confidence: 99%

Structure/Function Analysis of Recurrent Mutations in SETD2 Protein Reveals a Critical and Conserved Role for a SET Domain Residue in Maintaining Protein Stability and Histone H3 Lys-36 Trimethylation

Hacker

Fahey

Shinsky

et al. 2016

Journal of Biological Chemistry

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The yeast Set2 histone methyltransferase is a critical enzyme that plays a number of key roles in gene transcription and DNA repair. Recently, the human homologue, SETD2, was found to be recurrently mutated in a significant percentage of renal cell carcinomas, raising the possibility that the activity of SETD2 is tumorsuppressive. Using budding yeast and human cell line model systems, we examined the functional significance of two evolutionarily conserved residues in SETD2 that are recurrently mutated in human cancers. Whereas one of these mutations (R2510H), located in the Set2 Rpb1 interaction domain, did not result in an observable defect in SETD2 enzymatic function, a second mutation in the catalytic domain of this enzyme (R1625C) resulted in a complete loss of histone H3 Lys-36 trimethylation (H3K36me3). This mutant showed unchanged thermal stability as compared with the wild type protein but diminished binding to the histone H3 tail. Surprisingly, mutation of the conserved residue in Set2 (R195C) similarly resulted in a complete loss of H3K36me3 but did not affect dimethylated histone H3 Lys-36 (H3K36me2) or functions associated with H3K36me2 in yeast. Collectively, these data imply a critical role for Arg-1625 in maintaining the protein interaction with H3 and specific H3K36me3 function of this enzyme, which is conserved from yeast to humans. They also may provide a refined biochemical explanation for how H3K36me3 loss leads to genomic instability and cancer.Cancer is increasingly characterized by alterations in chromatin-modifying enzymes (1). SETD2, a non-redundant histone H3 lysine 36 (H3K36) 4 methyltransferase (2), has been found to be mutated in a growing list of tumor types, most notably in clear cell renal cell carcinoma (ccRCC) (1, 3, 4), but also in high grade gliomas (5), breast cancer (6), bladder cancer (7), and acute lymphoblastic leukemia (8 -10). Recent studies exploring intratumor heterogeneity in ccRCC identified distinct mutations in SETD2 from spatially distinct subsections of an individual tumor, suggesting that mutation of SETD2 is a critical and selected event in ccRCC cancer progression (11). Mutations in SETD2 are predominantly inactivating, such as early nonsense or frameshift mutations, which lead to nonfunctional protein and global loss of H3K36 trimethylation (H3K36me3) (4,11,12). Missense mutations tend to cluster in two domains (1,4,12,13): the SET domain, which catalyzes H3K36me3 (14), and the Set2 Rpb1 interaction (SRI) domain, which mediates the interaction between SETD2 and the hyperphosphorylated form of RNA polymerase II (RNAPII) (13).SETD2 and its yeast counterpart, Set2, both associate with RNAPII in a co-transcriptional manner (13,15,16). In yeast, Set2 mediates all H3K36 methylation states (H3K36me1/me2/ me3) (17) and regulates the recruitment of chromatin-remodeling enzymes (Isw1b) and a histone deacetylase (Rpd3) (18) that functions to keep gene bodies deacetylated, thereby maintaining a more compact chromatin structure (19,20) that is more resistant to inappropr...

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“…Depleting SET8 in mammalian cells attenuated the accumulation of 53BP1 at DSBs and also NHEJ activity, suggesting the importance of H4-K20 methylation for the progression of the 53BP1-dependent NHEJ repair pathway. Another HMT, SETD2 (yeast homolog: SET2), can contribute to DDRs through H3-K36 methylation (Pai et al, 2014;Pfister et al, 2014). Histone H3-K36 has been shown to be methylated by SET2 and acetylated by GCN5, and its methylation reduces chromatin accessibility and promotes the NHEJ repair pathway, while its acetylation increases accessibility and promotes the HR repair pathway.…”

Section: Introductionmentioning

confidence: 99%

“…Depletion of SET2 increases acetylation of H3-K36, chromatin accessibility and resection, while GCN5 deficiency results in the reverse phenotypes following DSB induction (Pai et al, 2014), suggesting that competition between methylation and acetylation of H3-K36 is important for repair pathway choice between NHEJ and HR. In the case of mammalian SETD2, this enzyme can interact with CtIP, a molecule which has been shown to play a role in the cellular response to DNA damage, and the interaction is important for CtIP recruitment to DSB sites and subsequent resection of DSB ends (Pfister et al, 2014). Depletion of SETD2 was demonstrated to reduce HR activity and increase aberrant resection related to microhomology-mediated end-joining (MMEJ).…”

Section: Introductionmentioning

confidence: 99%

Chromatin modification and NBS1: their relationship in DNA double-strand break repair

2015

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The importance of chromatin modification, including histone modification and chromatin remodeling, for DNA double-strand break (DSB) repair, as well as transcription and replication, has been elucidated. Phosphorylation of H2AX to γ-H2AX is one of the first responses following DSB detection, and this histone modification is important for the DSB damage response by triggering several events, including the accumulation of DNA damage response-related proteins and subsequent homologous recombination (HR) repair. The roles of other histone modifications such as acetylation, methylation and ubiquitination have also been recently clarified, particularly in the context of HR repair. NBS1 is a multifunctional protein that is involved in various DNA damage responses. Its recently identified binding partner RNF20 is an E3 ubiquitin ligase that facilitates the monoubiquitination of histone H2B, a process that is crucial for recruitment of the chromatin remodeler SNF2h to DSB damage sites. Evidence suggests that SNF2h functions in HR repair, probably through regulation of end-resection. Moreover, several recent reports have indicated that SNF2h can function in HR repair pathways as a histone remodeler and that other known histone remodelers can also participate in DSB damage responses. On the other hand, information about the roles of such chromatin modifications and NBS1 in non-homologous end joining (NHEJ) repair of DSBs and stalled fork-related damage responses is very limited; therefore, these aspects and processes need to be further studied to advance our understanding of the mechanisms and molecular players involved.

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SETD2-Dependent Histone H3K36 Trimethylation Is Required for Homologous Recombination Repair and Genome Stability

Cited by 396 publications

References 43 publications

DNA double strand break repair pathway choice: a chromatin based decision?

DNA double strand break repair pathway choice: a chromatin based decision?

Structure/Function Analysis of Recurrent Mutations in SETD2 Protein Reveals a Critical and Conserved Role for a SET Domain Residue in Maintaining Protein Stability and Histone H3 Lys-36 Trimethylation

Chromatin modification and NBS1: their relationship in DNA double-strand break repair

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