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 20 publications

(10 citation statements)

References 150 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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%

See 3 more Smart Citations

αKG-mediated carnitine synthesis promotes homologous recombination via histone acetylation

Uboveja,

Huang,

Buj

et al. 2024

Preprint

View full text Add to dashboard Cite

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.

show abstract

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

View full text Add to dashboard Cite

show abstract

“…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

View full text Add to dashboard Cite

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.

show abstract

Epigenetic regulation of Epstein–Barr virus: From bench to bedside

Gao,

Yang,

Cheng

et al. 2024

Clinical and Translational Dis

View full text Add to dashboard Cite

BackgroundEpstein–Barr virus (EBV) is a double‐stranded DNA herpesvirus and establishes life‐long infection in 95% of the world's populations.Main bodyEBV is critically involved in multiple diseases. Aberrant signaling pathways, immune escape, and metabolic reprogramming play essential roles in EBV‐mediated pathogenesis. However, the underlying mechanisms have not yet been fully elucidated. Here we reviewed recent advances on the epigenetic regulation of EBV pathogenesis, which may translate to potential therapeutic strategies in EBV‐associated diseases.ConclusionGrowing evidence has suggested that viral infections reconstruct epigenome to modulate gene expression both in the host and the virus levels.

show abstract

Histone post-translational modification and the DNA damage response

Cited by 20 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

Epigenetic regulation of Epstein–Barr virus: From bench to bedside

Contact Info

Product

Resources

About