Protective Mechanisms Against DNA Replication Stress in the Nervous System

Charlier, Clara Forrer; Martins, Rodrigo A. P.

doi:10.3390/genes11070730

Cited by 11 publications

(6 citation statements)

References 374 publications

(441 reference statements)

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“…Replication stress is a source of endogenous DNA damage in both cancers and neurodegenerative disorders ( 1 , 2 ). Two features of replication stress include high frequency of origin firing events and enhanced fork instability at natural replication barriers ( 1 ).…”

Section: Introductionmentioning

confidence: 99%

Elongating RNA polymerase II and RNA:DNA hybrids hinder fork progression and gene expression at sites of head-on replication-transcription collisions

Zardoni

Nardini

Brambati

et al. 2021

Nucleic Acids Research

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Uncoordinated clashes between replication forks and transcription cause replication stress and genome instability, which are hallmarks of cancer and neurodegeneration. Here, we investigate the outcomes of head-on replication-transcription collisions, using as a model system budding yeast mutants for the helicase Sen1, the ortholog of human Senataxin. We found that RNA Polymerase II accumulates together with RNA:DNA hybrids at sites of head-on collisions. The replication fork and RNA Polymerase II are both arrested during the clash, leading to DNA damage and, in the long run, the inhibition of gene expression. The inactivation of RNA Polymerase II elongation factors, such as the HMG-like protein Spt2 and the DISF and PAF complexes, but not alterations in chromatin structure, allows replication fork progression through transcribed regions. Attenuation of RNA Polymerase II elongation rescues RNA:DNA hybrid accumulation and DNA damage sensitivity caused by the absence of Sen1, but not of RNase H proteins, suggesting that such enzymes counteract toxic RNA:DNA hybrids at different stages of the cell cycle with Sen1 mainly acting in replication. We suggest that the main obstacle to replication fork progression is the elongating RNA Polymerase II engaged in an R-loop, rather than RNA:DNA hybrids per se or hybrid-associated chromatin modifications.

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Section: Introductionmentioning

confidence: 99%

Elongating RNA polymerase II and RNA:DNA hybrids hinder fork progression and gene expression at sites of head-on replication-transcription collisions

Zardoni

Nardini

Brambati

et al. 2021

Nucleic Acids Research

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“…The FA-BRCA pathway (FA pathway), involving various FANC genes, is essential for DNA damage response, particularly in repairing DNA inter-strand crosslinks, resulting in genome instability characterized by chromosomal breaks and radial figures ( Su and Huang, 2011 ). In brain development, the FA pathway ensures genomic integrity and NPCs survival during replicative stress ( Sii-Felice et al, 2008 ; Forrer Charlier and Martins, 2020 ). While BRCA1 contributes significantly to inhibition of apoptosis in NPCs ( Pao et al, 2014 ), FANCA is necessary for the maintenance and survival of neural stem cells (NSCs), contributing to the proper brain development ( Sii-Felice et al, 2008 ).…”

Section: Microcephaly Associated With Dna Damagementioning

confidence: 99%

DNA damage and repair: underlying mechanisms leading to microcephaly

Ribeiro,

Altinisik,

Rajan

et al. 2023

Front. Cell Dev. Biol.

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DNA-damaging agents and endogenous DNA damage constantly harm genome integrity. Under genotoxic stress conditions, the DNA damage response (DDR) machinery is crucial in repairing lesions and preventing mutations in the basic structure of the DNA. Different repair pathways are implicated in the resolution of such lesions. For instance, the non-homologous DNA end joining and homologous recombination pathways are central cellular mechanisms by which eukaryotic cells maintain genome integrity. However, defects in these pathways are often associated with neurological disorders, indicating the pivotal role of DDR in normal brain development. Moreover, the brain is the most sensitive organ affected by DNA-damaging agents compared to other tissues during the prenatal period. The accumulation of lesions is believed to induce cell death, reduce proliferation and premature differentiation of neural stem and progenitor cells, and reduce brain size (microcephaly). Microcephaly is mainly caused by genetic mutations, especially genes encoding proteins involved in centrosomes and DNA repair pathways. However, it can also be induced by exposure to ionizing radiation and intrauterine infections such as the Zika virus. This review explains mammalian cortical development and the major DNA repair pathways that may lead to microcephaly when impaired. Next, we discuss the mechanisms and possible exposures leading to DNA damage and p53 hyperactivation culminating in microcephaly.

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“…Exome sequencing of ASD hNPCs reveals mutations in several genes in the canonical Wnt pathway, cell-cycle regulation, mitotic checkpoints, and DNA repair, as well as in genes that maintain genomic stability ( ATM, BRACA1 CDK7, ERCC4 ). These recent studies indicate that DNA damage-induced replication stress is a key underlying mechanism of autism and possibly other neurodevelopmental disorders ( Charlier and Martins, 2020 ). DNA damage-induced replication stress might also be an important mechanism to explain how early-life exposure to environmental genotoxins induces long-term effects that lead to neurodegenerative disease.…”

Section: Genomic Instability and Cycad Toxinsmentioning

confidence: 99%

Genotoxic Damage During Brain Development Presages Prototypical Neurodegenerative Disease

Kisby

Spencer

2021

Front. Neurosci.

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Western Pacific Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex (ALS/PDC) is a disappearing prototypical neurodegenerative disorder (tau-dominated polyproteinopathy) linked with prior exposure to phytogenotoxins in cycad seed used for medicine and/or food. The principal cycad genotoxin, methylazoxymethanol (MAM), forms reactive carbon-centered ions that alkylate nucleic acids in fetal rodent brain and, depending on the timing of systemic administration, induces persistent developmental abnormalities of the cortex, hippocampus, cerebellum, and retina. Whereas administration of MAM prenatally or postnatally can produce animal models of epilepsy, schizophrenia or ataxia, administration to adult animals produces little effect on brain structure or function. The neurotoxic effects of MAM administered to rats during cortical brain development (specifically, gestation day 17) are used to model the histological, neurophysiological and behavioral deficits of human schizophrenia, a condition that may precede or follow clinical onset of motor neuron disease in subjects with sporadic ALS and ALS/PDC. While studies of migrants to and from communities impacted by ALS/PDC indicate the degenerative brain disorder may be acquired in juvenile and adult life, a proportion of indigenous cases shows neurodevelopmental aberrations in the cerebellum and retina consistent with MAM exposure in utero. MAM induces specific patterns of DNA damage and repair that associate with increased tau expression in primary rat neuronal cultures and with brain transcriptional changes that parallel those associated with human ALS and Alzheimer’s disease. We examine MAM in relation to neurodevelopment, epigenetic modification, DNA damage/replicative stress, genomic instability, somatic mutation, cell-cycle reentry and cellular senescence. Since the majority of neurodegenerative disease lacks a solely inherited genetic basis, research is needed to explore the hypothesis that early-life exposure to genotoxic agents may trigger or promote molecular events that culminate in neurodegeneration.

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Protective Mechanisms Against DNA Replication Stress in the Nervous System

Cited by 11 publications

References 374 publications

Elongating RNA polymerase II and RNA:DNA hybrids hinder fork progression and gene expression at sites of head-on replication-transcription collisions

Elongating RNA polymerase II and RNA:DNA hybrids hinder fork progression and gene expression at sites of head-on replication-transcription collisions

DNA damage and repair: underlying mechanisms leading to microcephaly

Genotoxic Damage During Brain Development Presages Prototypical Neurodegenerative Disease

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