Structural basis for proficient oxidized ribonucleotide insertion in double strand break repair

Jamsen, J.A.; Sassa, Akira; Perera, Lalith; Shock, David D.; Beard, William A.; Wilson, Samuel H.

doi:10.1038/s41467-021-24486-x

Cited by 11 publications

(11 citation statements)

References 54 publications

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“…ROS accumulation can impair DNA DSBs repair or homologous recombination. 7 , 8 , 36 During meiosis, DNA DSBs lead to phosphorylation of γH2AX by the activation of ataxia telangiectasia‐mutated (ATM) protein kinase. 24 Most DNA DSBs are repaired during the zygotene to pachytene stages except for the sex chromosomes, and some DSBs go through crossover resolution.…”

Section: Discussionmentioning

confidence: 99%

“… 6 Under normal physiological conditions, ROS oxidizes cellular nucleotide pools and causes DNA double‐strand breaks (DSBs), and DNA repair may occur downstream. 7 , 8 If DSBs are neither repaired nor removed, the DNA damage response triggers cell death. 9 , 10 On radiation exposure, PEX5 participated in DSBs repair and homologous recombination by consuming excessive ROS, 11 which protected hepatocellular carcinoma cells from radiation‐induced damage.…”

Section: Introductionmentioning

confidence: 99%

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Pre‐meiotic deletion of PEX5 causes spermatogenesis failure and infertility in mice

Liu

Song

et al. 2022

Cell Proliferation

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Peroxisomes are involved in the regulation of various pathological processes. Peroxisomal biogenesis factor 5 (PEX5), which plays an essential role in peroxisomal biogenesis, is critical for reactive oxygen species (ROS) accumulation. However, its underlying functions in spermatogenesis have not yet been identified. Pex5 was deleted by crossing Stra8‐Cre mice with Pex5flox/flox mice before the onset of meiosis. The morphology of testes and epididymides, spermatogenesis function, and fertility in both wild type (WT) and Pex5−/− mice were analysed by haematoxylin and eosin (HE) and immunofluorescent staining. Mechanism of PEX5 affecting peroxisomes and spermatogenesis were validated by Western blot and transmission electron microscopy (TEM). Transcriptome RNA sequencing (RNA‐seq) was used to profile the dysregulated genes in testes from WT and Pex5−/− mice on postnatal day (P) 35. The adult Pex5 knockout male mice were completely sterile with no mature sperm production. Loss of Pex5 in spermatocytes resulted in multinucleated giant cell formation, meiotic arrest, abnormal tubulin expression, and deformed acrosome formation. Furthermore, Pex5 deletion led to delayed DNA double‐strand break repair and improper crossover at the pachytene stage. Impaired peroxisome function in Pex5 knockout mice induced ROS redundancy, which in turn led to an increase in germ cell apoptosis and a decline in autophagy. Pex5 regulates ROS during meiosis and is essential for spermatogenesis and male fertility in mice.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pre‐meiotic deletion of PEX5 causes spermatogenesis failure and infertility in mice

Liu

Song

et al. 2022

Cell Proliferation

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“…Recent findings indicate that ribonucleotide incorporation into DNA (Pryor et al, 2018) and/or damage‐induced long non‐coding RNA (Michelini et al, 2017) promotes the successful processing of DSBs. In addition, oxidized ribonucleotides (8‐oxo‐rGTP) can be efficiently incorporated by DNA polymerase μ during DSB repair by NHEJ (Jamsen et al, 2021) resulting in substrates containing lesions in both DNA strands. Improved destruction of oxidized ribonucleoside triphosphates by overexpressed hMTH1 might reduce the incorporation of potentially inhibitory oxidized ribonucleotides, thereby promoting efficient DSB rejoining and preventing micronucleus formation.…”

Section: Discussionmentioning

confidence: 99%

Young transgenic hMTH1 mice are protected against dietary fat‐induced metabolic stress—implications for enhanced longevity

et al. 2022

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hMTH1 protects against mutation during oxidative stress. It degrades 8‐oxodGTP to exclude potentially mutagenic oxidized guanine from DNA. hMTH1 expression is linked to ageing. Its downregulation in cultured cells accelerates RAS‐induced senescence, and its overexpression in hMTH1‐Tg mice extends lifespan. In this study, we analysed the effects of a brief (5 weeks) high‐fat diet challenge (HFD) in young (2 months old) and adult (7 months old) wild‐type (WT) and hMTH1‐Tg mice. We report that at 2 months, hMTH1 overexpression ameliorated HFD‐induced weight gain, changes in liver metabolism related to mitochondrial dysfunction and oxidative stress. It prevented DNA damage as quantified by a comet assay. At 7 months old, these HFD‐induced effects were less severe and hMTH1‐Tg and WT mice responded similarly. hMTH1 overexpression conferred lifelong protection against micronucleus induction, however. Since the canonical activity of hMTH1 is mutation prevention, we conclude that hMTH1 protects young mice against HFD by reducing genome instability during the early period of rapid growth and maximal gene expression. hMTH1 protection is redundant in the largely non‐growing, differentiated tissues of adult mice. In hMTH1‐Tg mice, expression of a less heavily mutated genome throughout life provides a plausible explanation for their extended longevity.

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“…Both single-and double-stranded breaks (SSB and DSB) are a common feature of cell karyotype studies after cannabis exposure [7][8][9][10]12,13,99]. It therefore becomes important in the present context to note that the epigenome plays an often determinative role in influencing or selecting the site of DNA breakage generally [118][119][120][121][122][123][124][125][126][127][128][129][130][131], during meiotic crossing over [132][133][134][135][136][137][138][139], in the immune gene hypervariable region [140][141][142][143][144][145][146], and in oncogenic pathways [120,123,124,[147][148][149][150][151][152][153]…”

Section: Epigenomic Impacts On Dna Breakage Sitesmentioning

confidence: 99%

“…This tumor almost invariably involves the development of an isochromosome 12p. Its presence is explained by the concept of presumptive pericentromeric chromatin dysregulation as the dysregulated pericentromeric epigenome presumably facilitates the aberrant scission of the chromosome at the centromere, forming the isochromosome through the interactions between the epigenome and the genome as described above [118][119][120][121][122][123][124][125][126][127][128][129][130][131]. The presence of KIT and KRAS (and to a lesser extent NRAS) on chromosome 12 then confers a growth advantage on the mutant clone, and malignant tumorigenesis is the end result of this process continued in the context of the gross re-sculpting of the chromosomal landscape by repeated cycles of the breakage-fusion-bridge cycle across multiple cell divisions that accumulate over time.…”

Section: Cannabinoids Deliver Multiple Carcinogenic Insultsmentioning

confidence: 99%

Epidemiology of Δ8THC-Related Carcinogenesis in USA: A Panel Regression and Causal Inferential Study

Reece

Hulse

2022

IJERPH

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The use of Δ8THC is increasing at present across the USA in association with widespread cannabis legalization and the common notion that it is “legal weed”. As genotoxic actions have been described for many cannabinoids, we studied the cancer epidemiology of Δ8THC. Data on 34 cancer types was from the Centers for Disease Control Atlanta Georgia, substance abuse data from the Substance Abuse and Mental Health Services Administration, ethnicity and income data from the U.S. Census Bureau, and cannabinoid concentration data from the Drug Enforcement Agency, were combined and processed in R. Eight cancers (corpus uteri, liver, gastric cardia, breast and post-menopausal breast, anorectum, pancreas, and thyroid) were related to Δ8THC exposure on bivariate testing, and 18 (additionally, stomach, Hodgkins, and Non-Hodgkins lymphomas, ovary, cervix uteri, gall bladder, oropharynx, bladder, lung, esophagus, colorectal cancer, and all cancers (excluding non-melanoma skin cancer)) demonstrated positive average marginal effects on fully adjusted inverse probability weighted interactive panel regression. Many minimum E-Values (mEVs) were infinite. p-values rose from 8.04 × 10−78. Marginal effect calculations revealed that 18 Δ8THC-related cancers are predicted to lead to a further 8.58 cases/100,000 compared to 7.93 for alcoholism and −8.48 for tobacco. Results indicate that between 8 and 20/34 cancer types were associated with Δ8THC exposure, with very high effect sizes (mEVs) and marginal effects after adjustment exceeding tobacco and alcohol, fulfilling the epidemiological criteria of causality and suggesting a cannabinoid class effect. The inclusion of pediatric leukemias and testicular cancer herein demonstrates heritable malignant teratogenesis.

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Structural basis for proficient oxidized ribonucleotide insertion in double strand break repair

Cited by 11 publications

References 54 publications

Pre‐meiotic deletion of PEX5 causes spermatogenesis failure and infertility in mice

Pre‐meiotic deletion of PEX5 causes spermatogenesis failure and infertility in mice

Young transgenic hMTH1 mice are protected against dietary fat‐induced metabolic stress—implications for enhanced longevity

Epidemiology of Δ8THC-Related Carcinogenesis in USA: A Panel Regression and Causal Inferential Study

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