Balancing DNA repair to prevent ageing and cancer

Experimental Cell Research, Год журнала: 2021, Номер 405(2), С. 112679 - 112679

Опубликована: Июнь 5, 2021

DNA damage is a constant stressor to the cell. Persistent over time results in an increased risk of mutation and accumulation mutations with age. Loss efficient repair can lead accelerated ageing phenotypes or cancer risk, trade-off between susceptibility longevity often driven by cell's response damage. High levels mutants leads excessive cell death stem exhaustion which may promote premature ageing. Stem cells themselves have distinct characteristics that enable them retain low rates. However, when do arise, clonal expansion also contribute age-related tissue dysfunction as well heightened risk. In this review, we will highlight increasing hallmarks common both cancer. We propose anti-ageing interventions might be preventative discuss mechanisms through they act.

Язык: Английский

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Chromatin and the Cellular Response to Particle Radiation-Induced Oxidative and Clustered DNA Damage

Frontiers in Cell and Developmental Biology, Год журнала: 2022, Номер 10

Опубликована: Июль 13, 2022

Exposure to environmental ionizing radiation is prevalent, with greatest lifetime doses typically from high Linear Energy Transfer (high-LET) alpha particles via the radioactive decay of radon gas in indoor air. Particle highly genotoxic, inducing DNA damage including oxidative base lesions and double strand breaks. Due ionization density high-LET radiation, consequent clustered wherein ≥2 distinct occur within 1–2 helical turns one another. These multiply-damaged sites are difficult for eukaryotic cells resolve either quickly or accurately, resulting persistence and/or accumulation mutations at a greater rate per absorbed dose, relative lower LET types. The proximity same different types another challenging repair processes, diverse pathways often confounding interplaying complex ways. In this context, understanding state higher order chromatin compaction arrangements essential, as it influences produced by regulates recruitment activity factors. This review will summarize latest research exploring processes which induced, detected, repaired context chromatin.

Язык: Английский

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Positive and negative regulators of RAD51/DMC1 in homologous recombination and DNA replication

DNA repair, Год журнала: 2023, Номер 134, С. 103613 - 103613

Опубликована: Дек. 13, 2023

Язык: Английский

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Life in plastic, it’s fantastic! How Leishmania exploit genome instability to shape gene expression

Frontiers in Cellular and Infection Microbiology, Год журнала: 2023, Номер 13

Опубликована: Янв. 26, 2023

Leishmania are kinetoplastid pathogens that cause leishmaniasis, a debilitating and potentially life-threatening infection if untreated. Unusually, regulate their gene expression largely post-transcriptionally due to the arrangement of coding genes into polycistronic transcription units may contain 100s functionally unrelated genes. Yet, capable rapid responsive changes in challenging environments, often instead correlating with dynamic genome composition, ranging from chromosome copy number variations generation extrachromosomal DNA accumulation point mutations. Typically, such events indicate instability other eukaryotes, coinciding genetic abnormalities, but for , exploiting these products can provide selectable substrates catalyse necessary by modifying number. Unorthodox replication, repair, replication stress factors repeats recognised as contributors this intrinsic instability, how plasticity enhance fitness whilst limiting toxic under- or over-expression co-amplified co-transcribed is unclear. Herein, we focus on fresh, detailed insights improve our understanding . Furthermore, discuss emerging models circumvent regulatory issues arising transcription. Lastly, highlight key gaps future studies define, higher resolution, complex interactions.

Язык: Английский

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Conditional knockout of RAD51-related genes in Leishmania major reveals a critical role for homologous recombination during genome replication

PLoS Genetics, Год журнала: 2020, Номер 16(7), С. e1008828 - e1008828

Опубликована: Июль 1, 2020

Homologous recombination (HR) has an intimate relationship with genome replication, both during repair of DNA lesions that might prevent synthesis and in tackling stalls to the replication fork. Recent studies led us ask if HR have a more central role replicating Leishmania, eukaryotic parasite. Conflicting evidence emerged regarding whether or not genes are essential, genome-wide mapping provided for unorthodox organisation initiation sites, termed origins. To answer this question, we employed combined CRISPR/Cas9 DiCre approach rapidly generate assess effect conditional ablation RAD51 three RAD51-related proteins Leishmania major. Using approach, demonstrate loss any these factors is immediately lethal but each case growth slows time leads damage accumulation cells aberrant content. Despite similarities, show only RAD51-3 impairs causes elevated levels mutation. Furthermore, two act distinct ways, since RAD51, RAD51-3, profound on causing at major origins increased subtelomeres. Our work clarifies questions importance survival reveals unanticipated, programme microbial eukaryote.

Язык: Английский

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