Biological function and regulation of histone and non-histone lysine methylation in response to DNA damage

Chen, Yongcan; Zhu, Wei‐Guo

doi:10.1093/abbs/gmw050

Cited by 38 publications

(36 citation statements)

References 190 publications

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“…FoxM1 methylation by SETD3 adds a new regulatory dimension to this complex process. As many non-histone proteins in the human proteome are known to be methylated2728293031323334, we hypothesize that additional cellular factors that regulate the VEGF signaling under hypoxia may also be methylated by SETD3. Interestingly, two of the known VEGF receptors35, FLT1 (VEGFR1) and KDR (VEGFR2), were identified as SETD3 interacting proteins in our ProtoArray screen (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

Chromatin associated SETD3 negatively regulates VEGF expression

Cohn

Feldman

Weil

et al. 2016

Sci Rep

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SETD3 is a member of the protein lysine methyltransferase (PKMT) family, which catalyzes the addition of methyl group to lysine residues. Accumulating data suggest that PKMTs are involved in the regulation of a broad spectrum of biological processes by targeting histone and non-histone proteins. Using a proteomic approach, we have identified 172 new SETD3 interacting proteins. We show that SETD3 binds and methylates the transcription factor FoxM1, which has been previously shown to be associated with the regulation of VEGF expression. We further demonstrate that under hypoxic conditions SETD3 is down-regulated. Mechanistically, we find that under basal conditions, SETD3 and FoxM1 are enriched on the VEGF promoter. Dissociation of both SETD3 and FoxM1 from the VEGF promoter under hypoxia correlates with elevated expression of VEGF. Taken together, our data reveal a new SETD3-dependent methylation-based signaling pathway at chromatin that regulates VEGF expression under normoxic and hypoxic conditions.

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Section: Discussionmentioning

confidence: 99%

Chromatin associated SETD3 negatively regulates VEGF expression

Cohn

Feldman

Weil

et al. 2016

Sci Rep

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“…In recent years the role of epigenetic modifiers in regulation of the DNA double strand break repair, cell cycle checkpoints and ultimately cell survival has emerged. Several lysine methyltransferases (KMTs), including G9a, Dot1L, SMYD2, EZH2 and Set7/9, were shown to regulate patterns of gene expression and cell fate via modifying key lysine residues on histones (H3, H4, H2B), transcription factors (p53, NF-kB), cell cycle regulators (Rb) and signaling kinases (MAPKAPK3) [17, 18]. As a result, small molecule inhibitors targeting some of these enzymes (e.g.…”

Section: Introductionmentioning

confidence: 99%

SMYD2 lysine methyltransferase regulates leukemia cell growth and regeneration after genotoxic stress

et al. 2017

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The molecular determinants governing escape of Acute Myeloid Leukemia (AML) cells from DNA damaging therapy remain poorly defined and account for therapy failures. To isolate genes responsible for leukemia cells regeneration following multiple challenges with irradiation we performed a genome-wide shRNA screen. Some of the isolated hits are known players in the DNA damage response (e.g. p53, CHK2), whereas other, e.g. SMYD2 lysine methyltransferase (KMT), remains uncharacterized in the AML context. Here we report that SMYD2 knockdown confers relative resistance to human AML cells against multiple classes of DNA damaging agents. Induction of the transient quiescence state upon SMYD2 downregulation correlated with the resistance. We revealed that diminished SMYD2 expression resulted in the upregulation of the related methyltransferase SET7/9, suggesting compensatory relationships. Indeed, pharmacological targeting of SET7/9 with (R)-PFI2 inhibitor preferentially inhibited the growth of cells expressing low levels of SMYD2.Finally, decreased expression of SMYD2 in AML patients correlated with the reduced sensitivity to therapy and lower probability to achieve complete remission. We propose that the interplay between SMYD2 and SET7/9 levels shifts leukemia cells from growth to quiescence state that is associated with the higher resistance to DNA damaging agents and rationalize SET7/9 pharmacological targeting in AML.

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“…Histone methylation is regulated by a group of lysine methyltransferases (KMTs) and demethylases (KDMs), which have a high specificity to target different lysine residues. Various histone methylation sites are dynamically altered, either globally or locally upon DNA damage (Chen and Zhu 2016). One of the key histone methylation sites involved in ATM signaling is H3 lysine 9 (H3K9) ( Fig.…”

Section: Histone Methylationmentioning

confidence: 99%

Regulation of DNA damage-induced ATM activation by histone modifications

Chen

Tang

et al. 2019

GENOME INSTAB. DIS.

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Ataxia-telangiectasia mutated (ATM) is an apical kinase involved in the cellular response to DNA damage in eukaryotes, especially DNA double-strand breaks (DSBs). Upon DSB, ATM is activated through a hierarchy of well-organized cellular processes and machineries, including post-translational modifications (PTMs), the MRE11-RAD50-NBS1 (MRN) complex and chromatin perturbations. ATM activation initiates a cascade of chromatin modifications and nucleosome remodeling that permits the assembly of repair factors that ensure a highly orchestrated response to repair damaged DNA. Numerous studies have tried to elucidate the mechanisms of ATM activation, but how it is activated by DNA damage signals is still unclear. Histone modifications are considered essential for regulating ATM activation: a histone octamer constitutes the nucleosome core and histone tails protrude into the DNA strands to alter the chromatin landscape and DNA accessibility. Here, we summarize how histone modifications regulate ATM activation, with an emphasis on the functional relevance in DNA damage response and repair.

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Biological function and regulation of histone and non-histone lysine methylation in response to DNA damage

Cited by 38 publications

References 190 publications

Chromatin associated SETD3 negatively regulates VEGF expression

Chromatin associated SETD3 negatively regulates VEGF expression

SMYD2 lysine methyltransferase regulates leukemia cell growth and regeneration after genotoxic stress

Regulation of DNA damage-induced ATM activation by histone modifications

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