Histone post-translational modification and the DNA damage response

Song, Haoyun; Shen, Rong; Liu, Xiangwen; Yang, Xiaoyu; Xie, Kun; Zhao, Guo; Wang, Degui

doi:10.1016/j.gendis.2022.04.002

Cited by 10 publications

(10 citation statements)

References 150 publications

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“…Together, these data indicate the observed effects are due to an acetylation reaction. Prior studies have provided a link between histone acetylation and DNA repair proficiency (Gong and Miller, 2013;Song et al, 2023), and we observed an increase in histone acetylation downstream of aKG-mediated TMLHE (Fig. 3).…”

Section: Resultssupporting

confidence: 64%

“…3-4 ). Indeed, histone acetylation is implicated in promoting DNA damage response in multiple ways (Song et al, 2023). Histone acetylation plays a major role in regulating the chromatin structure around the DSB that is required for both chromatin relaxation and efficient recruitment of DSB repair proteins as well as promoting transcription of DNA repair genes.…”

Section: Discussionmentioning

confidence: 99%

“…Prior work has demonstrated that histone acetylation is necessary for HR-mediated DNA repair (Gong and Miller, 2013; Song et al, 2023). Carnitine functions as a carrier for acylgroups into and out of the mitochondria (Longo et al, 2016), and acetylcarnitine shuttling from the mitochondria and peroxisome can provide the acetyl groups for histone acetylation (Izzo et al, 2023; Kuna et al, 2023).…”

Section: Introductionmentioning

confidence: 99%

“…Epigenetic modifications such as histone tail post-translational modifications (PTMs) play a crucial role in many fundamental cellular processes including DNA DSB repair (Gong and Miller, 2013, 2019; Song et al, 2023). Interestingly, histone PTMs are metabolically sensitive (Izzo et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

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αKG-mediated carnitine synthesis promotes homologous recombination via histone acetylation

Uboveja,

Huang,

Buj

et al. 2024

Preprint

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Homologous recombination (HR) deficiency enhances sensitivity to DNA damaging agents commonly used to treat cancer. In HR-proficient cancers, metabolic mechanisms driving response or resistance to DNA damaging agents remain unclear. Here we identified that depletion of alpha-ketoglutarate (αKG) sensitizes HR-proficient cells to DNA damaging agents by metabolic regulation of histone acetylation. αKG is required for the activity of αKG-dependent dioxygenases (αKGDDs), and prior work has shown that changes in αKGDD affect demethylases. Using a targeted CRISPR knockout library consisting of 64 αKGDDs, we discovered that Trimethyllysine Hydroxylase Epsilon (TMLHE), the first and rate-limiting enzyme inde novocarnitine synthesis, is necessary for proliferation of HR-proficient cells in the presence of DNA damaging agents. Unexpectedly, αKG-mediated TMLHE-dependent carnitine synthesis was required for histone acetylation, while histone methylation was affected but dispensable. The increase in histone acetylation via αKG-dependent carnitine synthesis promoted HR-mediated DNA repair through site- and substrate-specific histone acetylation. These data demonstrate for the first time that HR-proficiency is mediated through αKG directly influencing histone acetylation via carnitine synthesis.

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Section: Resultssupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

αKG-mediated carnitine synthesis promotes homologous recombination via histone acetylation

Uboveja,

Huang,

Buj

et al. 2024

Preprint

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“…Restoring damaged DNA requires chromatin remodeling, which involves epigenetic modifications to histones (e.g., methylation or acetylation) [ 129 ]. These modifications may activate or inhibit gene clusters responsible for cancer cell survival [ 130 ].…”

Section: Chromatin Remodeling and Gene Transcriptionmentioning

confidence: 99%

The Implication of Topoisomerase II Inhibitors in Synthetic Lethality for Cancer Therapy

Matias-Barrios

Dong

2023

Pharmaceuticals

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DNA topoisomerase II (Top2) is essential for all eukaryotic cells in the regulation of DNA topology through the generation of temporary double-strand breaks. Cancer cells acquire enhanced Top2 functions to cope with the stress generated by transcription and DNA replication during rapid cell division since cancer driver genes such as Myc and EZH2 hijack Top2 in order to realize their oncogenic transcriptomes for cell growth and tumor progression. Inhibitors of Top2 are therefore designed to target Top2 to trap it on DNA, subsequently causing protein-linked DNA breaks, a halt to the cell cycle, and ultimately cell death. Despite the effectiveness of these inhibitors, cancer cells can develop resistance to them, thereby limiting their therapeutic utility. To maximize the therapeutic potential of Top2 inhibitors, combination therapies to co-target Top2 with DNA damage repair (DDR) machinery and oncogenic pathways have been proposed to induce synthetic lethality for more thorough tumor suppression. In this review, we will discuss the mode of action of Top2 inhibitors and their potential applications in cancer treatments.

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Applying multi‐omics toward tumor microbiome research

Zhang

Kandalai

Zhou

et al. 2023

iMeta

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Rather than a "short-term tenant," the tumor microbiome has been shown to play a vital role as a "permanent resident," affecting carcinogenesis, cancer development, metastasis, and cancer therapies. As the tumor microbiome has great potential to become a target for the early diagnosis and treatment of cancer, recent research on the relevance of the tumor microbiota has attracted a wide range of attention from various scientific fields, resulting in remarkable progress that benefits from the development of interdisciplinary technologies.However, there are still a great variety of challenges in this emerging area, such as the low biomass of intratumoral bacteria and unculturable character of some microbial species. Due to the complexity of tumor microbiome research (e.g., the heterogeneity of tumor microenvironment), new methods with high spatial and temporal resolution are urgently needed. Among these developing methods, multi-omics technologies (combinations of genomics, transcriptomics, proteomics, and metabolomics) are powerful approaches that can facilitate the understanding of the tumor microbiome on different levels of the central dogma. Therefore, multi-omics (especially single-cell omics) will make enormous impacts on the future studies of the interplay between microbes and tumor microenvironment. In this review, we have systematically summarized the advances in multi-omics and their existing and potential applications in tumor microbiome research, thus providing an omics toolbox for investigators to reference in the future.

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Histone post-translational modification and the DNA damage response

Cited by 10 publications

References 150 publications

αKG-mediated carnitine synthesis promotes homologous recombination via histone acetylation

αKG-mediated carnitine synthesis promotes homologous recombination via histone acetylation

The Implication of Topoisomerase II Inhibitors in Synthetic Lethality for Cancer Therapy

Applying multi‐omics toward tumor microbiome research

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