Covalent PARylation of DNA base excision repair proteins regulates DNA demethylation DOI Creative Commons
Simon D Schwarz,

Jianming Xu,

Kapila Gunasekera

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 2, 2024

Abstract The intracellular ATP-ribosyltransferases PARP1 and PARP2, contribute to DNA base excision repair (BER) demethylation have been implicated in epigenetic programming early mammalian development. Recently, proteomic analyses identified BER proteins be covalently poly-ADP-ribosylated by PARPs. role of this posttranslational modification the process is unknown. Here, we show that senses AP-sites SSBs generated during TET-TDG mediated active attaches PAR each protein engaged. Covalent PARylation dissociates from DNA, which accelerates completion process. Consistently, inhibition mESC resulted both reduced locus-specific TET-TDG-targeted demethylation, general random damage. Our findings establish a critical function covalent coordinating molecular processes associated with dynamic methylation.

Language: Английский

DNA single-strand break repair and human genetic disease DOI
Keith W. Caldecott

Trends in Cell Biology, Journal Year: 2022, Volume and Issue: 32(9), P. 733 - 745

Published: May 26, 2022

Language: Английский

Citations

110
Assessing and advancing the safety of CRISPR-Cas tools: from DNA to RNA editing DOI Creative Commons
Jianli Tao, Daniel E. Bauer, Roberto Chiarle

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Jan. 13, 2023

CRISPR-Cas gene editing has revolutionized experimental molecular biology over the past decade and holds great promise for treatment of human genetic diseases. Here we review development CRISPR-Cas9/Cas12/Cas13 nucleases, DNA base editors, prime RNA focusing on assessment improvement their precision safety, pushing limit specificity efficiency. We summarize capabilities limitations each CRISPR tool from to editing, highlight opportunities future improvements applications in basic research, as well therapeutic clinical considerations use patients.

Language: Английский

Citations

104
Inflammation and DNA damage: cause, effect or both DOI
Antonio Pezone, Fabiola Olivieri,

Maria Vittoria Napoli

et al.

Nature Reviews Rheumatology, Journal Year: 2023, Volume and Issue: 19(4), P. 200 - 211

Published: Feb. 7, 2023

Language: Английский

Citations

104
Insights into Alzheimer’s disease from single-cell genomic approaches DOI
Mitchell H. Murdock, Li‐Huei Tsai

Nature Neuroscience, Journal Year: 2023, Volume and Issue: 26(2), P. 181 - 195

Published: Jan. 2, 2023

Language: Английский

Citations

100
Genetics and neurobiology of eating disorders DOI
Cynthia M. Bulik, Jonathan R. I. Coleman,

J. Andrew Hardaway

et al.

Nature Neuroscience, Journal Year: 2022, Volume and Issue: 25(5), P. 543 - 554

Published: May 1, 2022

Language: Английский

Citations

89
A NPAS4–NuA4 complex couples synaptic activity to DNA repair DOI Creative Commons
Elizabeth A. Pollina,

Daniel T. Gilliam,

Andrew T. Landau

et al.

Nature, Journal Year: 2023, Volume and Issue: 614(7949), P. 732 - 741

Published: Feb. 15, 2023

Abstract Neuronal activity is crucial for adaptive circuit remodelling but poses an inherent risk to the stability of genome across long lifespan postmitotic neurons 1–5 . Whether have acquired specialized protection mechanisms that enable them withstand decades potentially damaging stimuli during periods heightened unknown. Here we identify activity-dependent DNA repair mechanism in which a new form NuA4–TIP60 chromatin modifier assembles activated around inducible, neuronal-specific transcription factor NPAS4. We purify this complex from brain and demonstrate its functions eliciting changes neuronal transcriptomes circuitry. By characterizing landscape activity-induced double-strand breaks brain, show NPAS4–NuA4 binds recurrently damaged regulatory elements recruits additional machinery stimulate their repair. Gene bound by are partially protected against age-dependent accumulation somatic mutations. Impaired signalling leads cascade cellular defects, including dysregulated transcriptional responses, loss control over inhibition instability, all culminate reduce organismal lifespan. In addition, mutations several components NuA4 reported lead neurodevelopmental autism spectrum disorders. Together, these findings couples directly preservation, disruption may contribute developmental disorders, neurodegeneration ageing.

Language: Английский

Citations

82
Mechanisms of DNA damage‐mediated neurotoxicity in neurodegenerative disease DOI Creative Commons
Gwyneth Welch, Li‐Huei Tsai

EMBO Reports, Journal Year: 2022, Volume and Issue: 23(6)

Published: May 2, 2022

Neurons are highly susceptible to DNA damage accumulation due their large energy requirements, elevated transcriptional activity, and long lifespan. While newer research has shown that breaks mutations may facilitate neuron diversity during development neuronal function throughout life, a wealth of evidence indicates deficient repair underlies many neurological disorders, especially age-associated neurodegenerative diseases. Recently, efforts clarify the molecular link between neurodegeneration have improved our understanding how genomic location defunct proteins impact health. Additionally, work establishing role for senescence in aging diseased brain reveals play central neuroinflammation associated with disease.

Language: Английский

Citations

80
Active DNA demethylation promotes cell fate specification and the DNA damage response DOI
Dongpeng Wang, Wei Wu, Elsa Callén

et al.

Science, Journal Year: 2022, Volume and Issue: 378(6623), P. 983 - 989

Published: Dec. 1, 2022

Neurons harbor high levels of single-strand DNA breaks (SSBs) that are targeted to neuronal enhancers, but the source this endogenous damage remains unclear. Using two systems postmitotic lineage specification-induced pluripotent stem cell-derived neurons and transdifferentiated macrophages-we show thymidine glycosylase (TDG)-driven excision methylcytosines oxidized with ten-eleven translocation enzymes (TET) is a SSBs. Although macrophage differentiation favors short-patch base repair fill in single-nucleotide gaps, also frequently use long-patch subpathway. Disrupting gap-filling process using anti-neoplastic cytosine analogs triggers response cell death, which dependent on TDG. Thus, TET-mediated active demethylation promotes damage, normally safeguards identity can provoke neurotoxicity after anticancer treatments.

Language: Английский

Citations

72
Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration DOI Creative Commons
Vishnu Dileep, Carles A. Boix, Hansruedi Mathys

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(20), P. 4404 - 4421.e20

Published: Sept. 1, 2023

Persistent DNA double-strand breaks (DSBs) in neurons are an early pathological hallmark of neurodegenerative diseases including Alzheimer's disease (AD), with the potential to disrupt genome integrity. We used single-nucleus RNA-seq human postmortem prefrontal cortex samples and found that excitatory AD were enriched for somatic mosaic gene fusions. Gene fusions particularly damage repair senescence signatures. In addition, structural variations burdened DSBs CK-p25 mouse model neurodegeneration. Neurons also had elevated levels cohesin along progressive multiscale disruption 3D organization aligned transcriptional changes synaptic, neuronal development, histone genes. Overall, this study demonstrates stability by as steps progression diseases.

Language: Английский

Citations

66
Causes and consequences of DNA single-strand breaks DOI Creative Commons
Keith W. Caldecott

Trends in Biochemical Sciences, Journal Year: 2023, Volume and Issue: 49(1), P. 68 - 78

Published: Nov. 30, 2023

DNA single-strand breaks (SSBs) are among the most common lesions arising in human cells, with tens to hundreds of thousands each cell, day. Cells have efficient mechanisms for sensing and repair these ubiquitous lesions, but failure processes rapidly remove SSBs can lead a variety pathogenic outcomes. The threat posed by unrepaired is illustrated existence at least six genetic diseases which SSB (SSBR) defective, all characterised neurodevelopmental and/or neurodegenerative pathology. Here, I review current understanding how arise impact on critical molecular processes, such as replication gene transcription, their links disease.

Language: Английский

Citations

44