A mechanism for oxidative damage repair at gene regulatory elements

Ray, Sujoy; Abugable, Arwa A.; Parker, Jacob; Liversidge, Kirsty; Palminha, Nelma M.; Liao, Chunyan; Acosta‐Martin, Adelina E.; Souza, Cleide dos Santos; Jurga, Mateusz; Sudbery, Ian; El‐Khamisy, Sherif F.

doi:10.1038/s41586-022-05217-8

Cited by 20 publications

(11 citation statements)

References 74 publications

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“…Our data also indicate that not only the origin of DSBs at promoters are different from gene body but also how these DSBs are processed, consisting with a recent report showing that promoters are prone to oxidative damage and are protected by NuMA (Ray et al ., 2022). These observations are proposing a model inwhich DNA damage and repair are subjected to different ‘rules’ at different regions across the gene.…”

Section: Discussionsupporting

confidence: 83%

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R-loops and Topoisomerase 1 facilitate formation of transcriptional DSBs at gene bodies of hypertranscribed cancer genes

Hidmi

Aqeilan

2022

Preprint

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DNA double-stranded breaks (DSBs) are considered the most deleterious type of DNA damage. Although cytotoxic levels of DSBs occur mainly due to external factors, such as ionizing irradiation and UV radiation, DSBs can occur naturally under physiological conditions through cell's natural processes such as transcription and replication. However, how physiological DSBs are generated during transcription is still poorly understood. Here, we mapped DSBs using in-suspension break labeling in situ and sequencing (sBLISS) and re-analysis of ChIP-seq and DRIP-seq data, along with immunofluorescence staining for DNA damage markers in MCF-7 cells. Mapping of DSBs revealed their occurrence at highly expressed genes that are enriched with Topoisomerase 1 (Top1), the main enzyme responsible for resolving positive and negative supercoiling, and with R-loops. Depleting R-loops and Top1 decreased DSBs specifically at highly expressed and Top1/R-loops-enriched genes implying that Top1 and R-loops are the main causes of transcriptional DSBs. These findings propose a model in which DSBs in highly expressed genes, mainly oncogenes, are caused by resolving of R-loops and the catalytic activity of Top1. Our data also reveal that these genes, despite being highly fragile, are covered by γ-H2AX suggesting efficient repair signaling. Our findings underscore the critical roles of Top1 and R-loops in regulating DSBs in hypertranscribed oncogenes implicated in carcinogenesis.

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Section: Discussionsupporting

confidence: 83%

“…A possible mechanism could be that R-loops and TOP1 themselves could accumulate SSBs at both strands leading to DSBs. Another posibility is that SSBs induced by TOP1 and R-loops could be adjacent to SSBs induced by other agents such as oxidative damage (Ray et al ., 2022).…”

Section: Discussionmentioning

confidence: 99%

R-loops and Topoisomerase 1 facilitate formation of transcriptional DSBs at gene bodies of hypertranscribed cancer genes

Hidmi

Aqeilan

2022

Preprint

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“…This may drive genome damage and prompts repair by recruiting X-ray repair cross-complementing protein 1 and PARP1. Yet, limiting the PARylation at the initiating polymerase II complexes is necessary for the transcription of immediate-early genes and depends on the activity of the nuclear mitotic apparatus protein NuMA [ 63 ]. The increased detection of M+5 ADPr after zymosan stimulation and the high expression of PARG mRNA suggest a wide recycling of poly(ADPr) to maintain a pattern of PARylated proteins consistent with the required phenotype and reliant on metabolic intermediates [ 59 , 60 ].…”

Section: Discussionmentioning

confidence: 99%

Central carbon metabolism exhibits unique characteristics during the handling of fungal patterns by monocyte-derived dendritic cells

Alvarez,

Mancebo,

Alonso

et al. 2024

Redox Biology

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“…These modifications could alter cellular function by regulating stability, activity, subcellular localization or the protein-protein interaction of oxidized proteins [2]. A wide range of cellular mechanisms are activated to eliminate ROS as well as the ROS-mediated oxidized biomolecules (such as the newly discovered protection of promoters from oxidative damage though the action of the nuclear mitotic apparatus protein, NuMA [3]). Nonetheless, upon persistent activation these mechanisms may either aggravate the cellular damage or become impaired, eventually leading to a vicious cycle that promotes the progression of several pathologies.…”

Section: Introductionmentioning

confidence: 99%

Oxidative Stress in Age-Related Neurodegenerative Diseases: An Overview of Recent Tools and Findings

2023

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Reactive oxygen species (ROS) have been described to induce a broad range of redox-dependent signaling reactions in physiological conditions. Nevertheless, an excessive accumulation of ROS leads to oxidative stress, which was traditionally considered as detrimental for cells and organisms, due to the oxidative damage they cause to biomolecules. During ageing, elevated ROS levels result in the accumulation of damaged proteins, which may exhibit altered enzymatic function or physical properties (e.g., aggregation propensity). Emerging evidence also highlights the relationship between oxidative stress and age-related pathologies, such as protein misfolding-based neurodegenerative diseases (e.g., Parkinson’s (PD), Alzheimer’s (AD) and Huntington’s (HD) diseases). In this review we aim to introduce the role of oxidative stress in physiology and pathology and then focus on the state-of-the-art techniques available to detect and quantify ROS and oxidized proteins in live cells and in vivo, providing a guide to those aiming to characterize the role of oxidative stress in ageing and neurodegenerative diseases. Lastly, we discuss recently published data on the role of oxidative stress in neurological disorders.

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A mechanism for oxidative damage repair at gene regulatory elements

Cited by 20 publications

References 74 publications

R-loops and Topoisomerase 1 facilitate formation of transcriptional DSBs at gene bodies of hypertranscribed cancer genes

R-loops and Topoisomerase 1 facilitate formation of transcriptional DSBs at gene bodies of hypertranscribed cancer genes

Central carbon metabolism exhibits unique characteristics during the handling of fungal patterns by monocyte-derived dendritic cells

Oxidative Stress in Age-Related Neurodegenerative Diseases: An Overview of Recent Tools and Findings

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