Chromatin modifications during repair of environmental exposure‐induced DNA damage: A potential mechanism for stable epigenetic alterations

O’Hagan, Heather M.

doi:10.1002/em.21830

Cited by 47 publications

(34 citation statements)

References 165 publications

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“…Following DNA damage, local chromatin structure has to be reorganized in order to protect DNA from exonucleases attack and permit the incorporation of several proteins that are sequentially implicated in different steps of specific DNA repair processes. [1][2][3] Their initial access of these proteins to damaged DNA is allowed by histone acetylation that facilitates chromatin relaxation, 4 access to specific proteins, 5 and the recruitment of Tip60 6 that acetylates ATM. 7,8 Immediately after DNA damage, there is an early phosphorylation of histone H2AX in Ser139 at damage sites.…”

Section: Introductionmentioning

confidence: 99%

VRK1 chromatin kinase phosphorylates H2AX and is required for foci formation induced by DNA damage

et al. 2015

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All types of DNA damage cause a local alteration and relaxation of chromatin structure. Sensing and reacting to this initial chromatin alteration is a necessary trigger for any type of DNA damage response (DDR). In this context, chromatin kinases are likely candidates to participate in detection and reaction to a locally altered chromatin as a consequence of DNA damage and, thus, initiate the appropriate cellular response. In this work, we demonstrate that VRK1 is a nucleosomal chromatin kinase and that its depletion causes loss of histones H3 and H4 acetylation, which are required for chromatin relaxation, both in basal conditions and after DNA damage, independently of ATM. Moreover, VRK1 directly and stably interacts with histones H2AX and H3 in basal conditions. In response to DNA damage induced by ionizing radiation, histone H2AX is phosphorylated in Ser139 by VRK1. The phosphorylation of H2AX and the formation of gH2AX foci induced by ionizing radiation (IR), are prevented by VRK1 depletion and are rescued by kinase-active, but not kinase-dead, VRK1. In conclusion, we found that VRK1 is a novel chromatin component that reacts to its alterations and participates very early in DDR, functioning by itself or in cooperation with ATM.

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Section: Introductionmentioning

confidence: 99%

VRK1 chromatin kinase phosphorylates H2AX and is required for foci formation induced by DNA damage

et al. 2015

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“…DNA damage itself causes programmed changes in noncoding RNAs, and a large number of miRNAs are transcriptionally induced upon DNA damage [54] . However, it is not clear what proportion of these alterations are reversed or are retained as epimutations after the external sources of damage are removed upon repair of the DNA damages [55] . Mutations in isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) are frequent in several types of cancer and they can cause epigenetic alterations.…”

Section: Other Causes Of Epigenetic Alterationsmentioning

confidence: 99%

Epigenetic reduction of DNA repair in progression to gastrointestinal cancer

Bernstein

2015

WJGO

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Deficiencies in DNA repair due to inherited germ-line mutations in DNA repair genes cause increased risk of gastrointestinal (GI) cancer. In sporadic GI cancers, mutations in DNA repair genes are relatively rare. However, epigenetic alterations that reduce expression of DNA repair genes are frequent in sporadic GI cancers. These epigenetic reductions are also found in field defects that give rise to cancers. Reduced DNA repair likely allows excessive DNA damages to accumulate in somatic cells. Then either inaccurate translesion synthesis past the un-repaired DNA damages or error-prone DNA repair can cause mutations. Erroneous DNA repair can also cause epigenetic alterations (i.e., epimutations, transmitted through multiple replication cycles). Some of these mutations and epimutations may cause progression to cancer. Thus, deficient or absent DNA repair is likely an important underlying cause of cancer. Whole genome sequencing of GI cancers show that between thousands to hundreds of thousands of mutations occur in these cancers. Epimutations that reduce DNA repair gene expression and occur early in progression to GI cancers are a likely source of this high genomic instability. Cancer cells deficient in DNA repair are more vulnerable than normal cells to inactivation by DNA damaging agents. Thus, some of the most clinically effective chemotherapeutic agents in cancer treatment are DNA damaging agents, and their effectiveness often depends on deficient DNA repair in cancer cells. Recently, at least 18 DNA repair proteins, each active in one of six DNA repair pathways, were found to be subject to epigenetic reduction of expression in GI cancers. Different DNA repair pathways repair different types of DNA damage. Evaluation of which DNA repair pathway(s) are deficient in particular types of GI cancer and/or particular patients may prove useful in guiding choice of therapeutic agents in cancer therapy.

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“…But how do the toxic agents intricate teratogenesis, carcinogenesis and mutagenesis in targeted tissues? This may be due to the fact that toxicants involve initiation or inhibit intracellular signaling cascades that trigger acetylation, deacetylation, and methylation of histones leading to DNA damage by epigenetic modification of chromatin [33]. All these events may happen due to the fact that these toxicants disturb gap junction intercellular communication (GJIC) that maintains tissue homeostasis and controls cellular function, such as growth, differentiation, development, and apoptosis.…”

Section: Tripathy and Mohantymentioning

confidence: 99%

Mesenchymal Stem Cells: An Innovative Approach in Pharmacokinetics

Tripathy¹,

Mohanty²

2017

Asian J Pharm Clin Res

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Multipotent mesenchymal stem cells (MSCs) are special kind of stem cells which originate from mesenchyme. These cells can be used as an imperative tool to study reproductive toxicity, carcinogenicity, mutagenicity, genotoxicity, and pharmacokinetics. This novel system may reveal toxicantinduced etiology, decipher detailed understanding on molecular mechanisms of toxicants induced pathways and also enumerate the safe dose of an investigational product. Hence, this could ultimately replace, improve or overtake current predictive models in toxicology. The particular review describes the utilization of MSCs in different field of toxicological and pharmacological research.

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Chromatin modifications during repair of environmental exposure‐induced DNA damage: A potential mechanism for stable epigenetic alterations

Cited by 47 publications

References 165 publications

VRK1 chromatin kinase phosphorylates H2AX and is required for foci formation induced by DNA damage

VRK1 chromatin kinase phosphorylates H2AX and is required for foci formation induced by DNA damage

Epigenetic reduction of DNA repair in progression to gastrointestinal cancer

Mesenchymal Stem Cells: An Innovative Approach in Pharmacokinetics

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