The emerging role of lysine demethylases in DNA damage response: dissecting the recruitment mode of KDM4D/JMJD2D to DNA damage sites

Khoury-Haddad, Hanan; Nadar‐Ponniah, Prathamesh T; Awwad, Samah W.; Ayoub, Nabieh

doi:10.1080/15384101.2015.1014147

Cited by 48 publications

(28 citation statements)

References 104 publications

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“…7 This mutant, which can no longer bind RNA, failed to accumulate at DNA damage sites, indicating that KDM4D-RNA interaction is required for its DNA damage accumulation. 6 Altogether, these studies implicate PARP1 and yet unidentified RNA molecules in regulating KDM4D function in the DDR.…”

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confidence: 92%

“…KDM4D PAR-binding region was mapped to residues 350-474. 6 This region contains the residues (E357/R450/R451/R455) that are essential for KDM4D PARylation and assembly at sites of DNA damage. 4 A fragment of KDM4D (residues 1-474), containing the PAR-binding domain (residues 350-474), showed a minor and transient accumulation at DNA damage sites.…”

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confidence: 99%

“…Moreover, further studies are needed to reveal PARP1-depenedent KDM4D partners at DSB sites. Furthermore, they tested the effect of KDM4D-RNA interaction on its recruitment to DNA damage sites, 6 since KDM4D chromatin localization is RNA-dependent. Mutating His115/ 219, Arg222/225/228/236/123 and Lys127 of KDM4D results in loss of RNA and chromatin binding.…”

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confidence: 99%

“…6 It is yet to be determined whether the binding of KDM4D to PAR moieties is critical for its recruitment to DNA damage sites. Moreover, further studies are needed to reveal PARP1-depenedent KDM4D partners at DSB sites.…”

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confidence: 99%

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KDM4D crosstalks with PARP1 and RNA at DNA DSBs

Goldberg

2015

Cell Cycle

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confidence: 92%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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KDM4D crosstalks with PARP1 and RNA at DNA DSBs

Goldberg

2015

Cell Cycle

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“…Previous studies showed that KDM4D can be swiftly recruited to DNA damage sites in a PARP1-dependent manner and facilitate double-strand break repair in human cells, which ensure efficient repair of DNA lesions to maintain genome stability [20,21]. KDM4D is also a novel cofactor of androgen receptor since it interacts with androgen receptor and stimulates its ability to up-regulate transcription, which plays an indispensable role in prostate cancer [22].…”

Section: Introductionmentioning

confidence: 99%

The Histone Demethylase KDM4D Promotes Hepatic Fibrogenesis by Modulating Toll-Like Receptor 4 Signaling Pathway

Dong

Jiang

et al. 2018

Preprint

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Potential conflict of interest: Nothing to report.Abbreviations: HSC, hepatic stellate cell; H3K9, histone H3 on lysine 9; TLR4, Toll-like receptor 4; α-SMA, α-smooth muscle actin; KMT, lysine methyltransferase; KDM, lysine demethylase; KDM4, lysine (K)-specific demethylase 4; qRT-PCR, quantitative real-time PCR; siRNA, small interfering RNA; FBS, fetal bovine serum; i.p., intraperitoneally; CCl 4 , carbon tetrachloride; TAA, thioacetamide; BDL, bile duct ligation; AAV, adeno-associated virus;shRNA, short-hairpin RNA; ALT, alanine aminotransferase; H&E, hematoxylin-eosin; ChIP, chromatin immunoprecipitation; DMEM, Dulbecco's Modified Eagle's Medium; H3K9me2, histone di-methyl-H3K9; IHC, immunohistochemistry; NF-κB, nuclear factor kappa B; MyD88, myeloid differentiation factor 88; GFP, green fluorescent protein.3 AbstractAccumulating evidence has revealed the pivotal role of epigenetic regulation in the pathogenesis of liver disease. However, the epigenetic mechanism that accounts for hepatic stellate cells (HSCs) activation in liver fibrosis remains largely unknown. In this study, primaryHSCs were used to screen the differentially expressed histone H3 lysine methyltransferases and demethylases during HSC activation. KDM4D was identified as a remarkable upregulated histone H3 demethylase during HSC activation. The overexpression profile of KDM4D was further confirmed in three fibrosis animal models and human fibrotic liver tissues. In vitro genetic silencing of Kdm4d impaired the collagen gel contraction and migration capacity of primary HSCs. In established CCl 4 -induced mice model, Kdm4d knockdown inhibited fibrosis progression, and promoted fibrosis reversal, with enhanced thinning and splitting of fibrotic septa, as well as a dramatic decrease in collagen area. Whole gene transcriptome analysis showed the regulatory role of KDM4D in Toll-Like Receptor (TLR) signaling pathway. Mechanistically, KDM4D catalyzed histone 3 on lysine 9 (H3K9) di-, and tri-demethylation, which promoted TLR4 expression, and subsequently prompted liver fibrogenesis by activating NF-κB signaling pathways. Conclusion: KDM4D facilitates TLR4 transcription through demethylation of H3K9, thus activating TLR4/NF-κB signaling pathways in HSCs, contributing to HSC activation and collagen crosslinking, further, hepatic fibrosis progression.

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T Cells Spatially Regulate B Cell Receptor Signaling in Lymphomas through H3K9me3 Modifications

Britto,

Balasubramani,

Desai

et al. 2024

Adv Healthcare Materials

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Activated B cell‐like diffuse large B‐cell lymphoma (ABC‐DLBCL) is a subtype associated with poor survival outcomes. Despite identifying therapeutic targets through molecular characterization, targeted therapies have limited success. New strategies using immune‐competent tissue models are needed to understand how DLBCL cells evade treatment. Here, synthetic hydrogel‐based lymphoma organoids were used to demonstrate how signals in the lymphoid tumor microenvironment (Ly‐TME) can alter B cell receptor (BCR) signaling and specific histone modifications, tri‐methylation of histone 3 at lysine 9 (H3K9me3), dampening the effects of BCR pathway inhibition. Using imaging modalities, T cells increased DNA methyltransferase 3A expression and cytoskeleton formation in proximal ABC‐DLCBL cells, regulated by H3K9me3. Expansion microscopy on lymphoma organoids revealed T cells increased the size and quantity of segregated H3K9me3 clusters in ABC‐DLBCL cells. Our findings suggest re‐organization of higher‐order chromatin structures that may contribute to evasion or resistance to therapy via the emergence of novel transcriptional states. Treating ABC‐DLBCL cells with a G9α histone methyltransferase inhibitor reversed T cell‐mediated modulation of H3K9me3 and overcame T cell‐mediated attenuation of treatment response to BCR pathway inhibition. This study emphasized the Ly‐TME's role in altering DLBCL fate and suggests targeting aberrant signaling and microenvironmental cross‐talk could benefit high‐risk patients.This article is protected by copyright. All rights reserved

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The emerging role of lysine demethylases in DNA damage response: dissecting the recruitment mode of KDM4D/JMJD2D to DNA damage sites

Cited by 48 publications

References 104 publications

KDM4D crosstalks with PARP1 and RNA at DNA DSBs

KDM4D crosstalks with PARP1 and RNA at DNA DSBs

The Histone Demethylase KDM4D Promotes Hepatic Fibrogenesis by Modulating Toll-Like Receptor 4 Signaling Pathway

T Cells Spatially Regulate B Cell Receptor Signaling in Lymphomas through H3K9me3 Modifications

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