DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases

Bettencourt, Conceição; Hensman-Moss, Davina; Flower, Michael; Wiethoff, Sarah; Brice, Alexis; Goizet, Cyril; Stevanin, Giovanni; Koutsis, Georgios; Karadima, Georgia; Πάνας, Μάριος; Yescas-Gómez, Petra; García‐Velázquez, Lizbeth; Alonso-Vilatela, María Elisa; Lima, Manuela; Raposo, Mafalda; Traynor, Bryan J.; Sweeney, Mary G.; Wood, Nicholas W.; Giunti, Paola; Dürr, Alexandra; Holmans, Peter Alan; Houlden, Henry; Tabrizi, Sarah J.; Jones, Lesley

doi:10.1002/ana.24656

Cited by 197 publications

(207 citation statements)

References 41 publications

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“…Remarkably, suppression of somatic instability delayed the phenotype in a mouse model . In GWAS analysis of CAG repeat disorders as a whole, DNA repair genes were associated with onset age, further suggesting the importance of somatic expansion . Somatic instability may influence the rate of progression, with a coding MSH3 variant having the strongest association in a GWAS .…”

Section: Evidence For a Role Of Somatic Mutations In Neurodegenerationmentioning

confidence: 99%

Review: Somatic mutations in neurodegeneration

Leija‐Salazar

Piette

Proukakis

2018

Neuropathology Appl Neurobio

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Somatic mutations are postzygotic mutations which may lead to mosaicism, the presence of cells with genetic differences in an organism. Their role in cancer is well established, but detailed investigation in health and other diseases has only been recently possible. This has been empowered by the improvements of sequencing techniques, including single‐cell sequencing, which can still be error‐prone but is rapidly improving. Mosaicism appears relatively common in the human body, including the normal brain, probably arising in early development, but also potentially during ageing. In this review, we first discuss theoretical considerations and current evidence relevant to somatic mutations in the brain. We present a framework to explain how they may be integrated with current views on neurodegeneration, focusing mainly on sporadic late‐onset neurodegenerative diseases (Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis). We review the relevant studies so far, with the first evidence emerging in Alzheimer's in particular. We also discuss the role of mosaicism in inherited neurodegenerative disorders, particularly somatic instability of tandem repeats. We summarize existing views and data to present a model whereby the time of origin and spatial distribution of relevant somatic mutations, combined with any additional risk factors, may partly determine the development and onset age of sporadic neurodegenerative diseases.

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Section: Evidence For a Role Of Somatic Mutations In Neurodegenerationmentioning

confidence: 99%

Review: Somatic mutations in neurodegeneration

Leija‐Salazar

Piette

Proukakis

2018

Neuropathology Appl Neurobio

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“…Insights into these underlying pathways could potentially serve as a target for drug manipulation. Subsequently, genotyping of these single nucleotide polymorphisms (SNP) in patients with CAG repeat disease (consisting of 1017 SCA patients), showed a significant association between DNA repair genes and the age at onset of SCA and HD, with SNPs in FAN1, PMS2 and RRM2B reaching the lowest Pvalues [30]. It has been suggested that common genetic variants, with a significant effect size, may act as genetic modifiers in rare Mendelian conditions such as the SCAs.…”

Section: The Identification Of Genetic Modifiersmentioning

confidence: 99%

“…The integrity of FAN1 is speculated to play a role in preventing TNR expansion [30]. FAN1 is a repair nuclease that is recruited to sites of cross link damage.…”

Section: Cross Link Repairmentioning

confidence: 99%

DNA repair in trinucleotide repeat ataxias

et al. 2018

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The inherited cerebellar ataxias comprise of a genetic heterogeneous group of disorders. Pathogenic expansions of cytosine-adenine-guanine (CAG) encoding polyglutamine tracts account for the largest proportion of autosomal dominant cerebellar ataxias, while GAA expansion in the first introns of frataxin gene is the commonest cause of autosomal recessive cerebellar ataxias. Currently, there is no available treatment to alter the disease trajectory, with devastating consequences for affected individuals. Inter- and Intrafamily phenotypic variability suggest the existence of genetic modifiers, which may become targets amendable to treatment. Recent studies have demonstrated the importance of DNA repair pathways in modifying spinocerebellar ataxia with CAG repeat expansions. In this review, we discuss the mechanisms in which DNA repair pathways, epigenetics and other genetic factors may act as modifiers in cerebellar ataxias due to trinucleotide repeat expansions.

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“…In addition to KIN (24), mutations in FAN1 have been associated with predisposition to colorectal and pancreatic cancer as well as autism and schizophrenia (28)(29)(30)(31), raising the possibility that defects in ICL repair may be associated with a wide variety of diseases. In vitro studies showed that human FAN1 can degrade ICL-containing oligonucleotides past the lesion in replication-like intermediates, thereby unhooking the ICLs (32)(33)(34).…”

Section: Dna Synthesis (Tls) and The Second Strand Is Repaired By Hommentioning

confidence: 99%

Structural mechanism of DNA interstrand cross-link unhooking by the bacterial FAN1 nuclease

Jin

Roy

Lee

et al. 2018

Journal of Biological Chemistry

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The mechanism of ICL unhooking by bacterial FAN1 4 a "head to tail" dimer in the presence of DNA (34).The authors suggest that FAN1 dimer scans, latches, and unwinds DNA to pull the single-stranded DNA to the active site of a FAN1. Mutations of the residues at the dimeric interface abolished the nuclease activity of the HsFAN1, raising the possibility that the dimerization is important for its activity.Bacterial FAN1 homologs share a high similarity with HsFAN1 (Fig. 1A, 23,35). Second, PaFAN1 does not have a specific basic pocket that is critical for the proposed "3-nt exonuclease" mechanism (Fig. 1B, C, 33). Third, PaFAN1 lacks the basic motif in the SAP domain required for dimerization in one of the structures of the human nuclease (Fig. 1A, 34). These features raise the question if PaFAN1 can unhook ICLs, and if so, by which mechanism.To address these issues, we examined the ICL Based on these findings, we provide insights into how FAN1 might have evolved to have two basic regions to guide its nuclease activity and maintain genomic stability. RESULTS Substrate specificity of PaFAN1In previous study, we have used a DNA substrate with a four nucleotide 5' flap (23). (Fig. S1E-F). PaFAN1 efficiently incises ICL lesionTo examine whether the bacterial FAN1homolog shares the ICL resolving activity of mammalian FAN1, we examined the in vitro ICL unhooking activity of PaFAN1 using various DNA ICL substrates (Fig. 1D). We first analyzed ifPaFAN1 can unhook the ICL near the ss/ds junction.We used DNA substrates containing a nitrogen-like ICL, which is free of duplex distortion (15,36,37), The mechanism of ICL unhooking by bacterial FAN1 7 how PaFAN1 can catalyze multiple cleavage events.

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DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases

Cited by 197 publications

References 41 publications

Review: Somatic mutations in neurodegeneration

Review: Somatic mutations in neurodegeneration

DNA repair in trinucleotide repeat ataxias

Structural mechanism of DNA interstrand cross-link unhooking by the bacterial FAN1 nuclease

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