Expandable DNA repeats and human disease

Mirkin, Sergei M.

doi:10.1038/nature05977

Cited by 844 publications

(1,011 citation statements)

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“…This is in agreement with the recent finding that repetitive DNA sequences with a propensity to form non-B DNA structures induce reversal of traversing replication forks at remarkably high frequencies (29). Considering the high number of endogenous DNA lesions (30) and the abundance of non-B-forming structures in the human genome (31), it is conceivable that fine-tuning of PAR synthesis and degradation at a number of chromosomal locations plays a pivotal role in assisting complete and faithful replication of the human genome. These observations may contribute to explain the mitotic defects previously associated with the essential role of PARG in development, as deletion of all isoforms of PARG leads to embryonic lethality in mice (29).…”

Section: Discussionsupporting

confidence: 80%

Poly(ADP-Ribosyl) Glycohydrolase Prevents the Accumulation of Unusual Replication Structures during Unperturbed S Phase

Chaudhuri

Ahuja

Herrador

et al. 2015

Molecular and Cellular Biology

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Poly(ADP-ribosyl)ation (PAR) has been implicated in various aspects of the cellular response to DNA damage and genome stability. Although 17 human poly(ADP-ribose) polymerase (PARP) genes have been identified, a single poly(ADP-ribosyl) glycohydrolase (PARG) mediates PAR degradation. Here we investigated the role of PARG in the replication of human chromosomes. We show that PARG depletion affects cell proliferation and DNA synthesis, leading to replication-coupled H2AX phosphorylation. Furthermore, PARG depletion or inhibition per se slows down individual replication forks similarly to mild chemotherapeutic treatment. Electron microscopic analysis of replication intermediates reveals marked accumulation of reversed forks and single-stranded DNA (ssDNA) gaps in unperturbed PARG-defective cells. Intriguingly, while we found no physical evidence for chromosomal breakage, PARG-defective cells displayed both ataxia-telangiectasia-mutated (ATM) and ataxia-Rad3-related (ATR) activation, as well as chromatin recruitment of standard double-strand-break-repair factors, such as 53BP1 and RAD51. Overall, these data prove PAR degradation to be essential to promote resumption of replication at endogenous and exogenous lesions, preventing idle recruitment of repair factors to remodeled replication forks. Furthermore, they suggest that fork remodeling and restarting are surprisingly frequent in unperturbed cells and provide a molecular rationale to explore PARG inhibition in cancer chemotherapy.C ellular responses are crucial for the adaptability and survival of a cell exposed to different types of endogenous and exogenous stress. The DNA damage response (DDR) consists of one such defense mechanism in response to different types of insults to the DNA. Poly(ADP)ribosylation of proteins is one of the quickest cellular responses to DNA damage and is brought about by proteins of the poly(ADP) ribose polymerase family (PARP), mostly PARP1 (1). Upon being recruited to sites of the DNA damage, NAD ϩ is used as a substrate by PARP to synthesize negatively charged poly(ADP-ribosyl)ation (PAR) polymers onto itself and also its target proteins (1). Through this posttranslational modification, PARP targets a variety of nuclear proteins to facilitate the recruitment of DNA repair factors to sites of damage (2, 3). Accordingly, PARP-1 or PARP-2-deficient mice and mouse embryonic fibroblasts show chromosomal aberrations and various DNA repair defects (4-6).Inhibition of PARP has become a promising therapeutic approach for the treatment of certain types of cancer (7). It was shown that PARP inhibitors could selectively kill homologous recombination (HR)-deficient cancer cells (8, 9). The reason behind the sensitivity of HR-deficient cells to PARP inhibition is thought to be the accumulation of single-stranded DNA (ssDNA) breaks in the absence of PAR synthesis, leading to replication fork collapse and double-stranded breaks (DSBs), which would then require HR factors for repair (8,10). Recently, PARP activity has also been reported to play a ro...

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Section: Discussionsupporting

confidence: 80%

Poly(ADP-Ribosyl) Glycohydrolase Prevents the Accumulation of Unusual Replication Structures during Unperturbed S Phase

Chaudhuri

Ahuja

Herrador

et al. 2015

Molecular and Cellular Biology

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“…The formation of non-B structures can lead to strand slippage and thereby repeat expansion during DNA replication [25]. In addition to the non-B DNA hairpins [9], triplexes [26], and tetraplexes [11] formed by short tandem repeats, the dumbbell structures observed in the present study also serve as a structural intermediate resulting from strand slippage, providing insights into the underlying molecular mechanisms of repeat expansion diseases.…”

Section: (Ttta) 2 Forms a Mini Dumbbell Structure Composed Of Two Tt mentioning

confidence: 84%

Unusual structures of TTTA repeats in icaC gene of Staphylococcus aureus

Guo

Lam

2015

FEBS Letters

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a b s t r a c tOne and two TTTA repeat expansions have been found in the coding region of icaC gene of Staphylococcus aureus variants which influence the expression of IcaC protein and alter the phenotype. Yet, the mechanism of these small-size TTTA repeat expansions remains unclear. In this study, we performed high-resolution nuclear magnetic resonance spectroscopic studies on TTTA repeats. Our results show that a DNA sequence containing three TTTA repeats can fold into dumbbell structures with a 3 0 or 5 0 -overhang. Exchange of these dumbbells makes the sequence behave like a 2-nt TT mini-loop at 25°C. The occurrence of these mini-loop and dumbbell structures in the nascent strand during DNA replication provides possible mechanistic pathways which account for one and two repeat expansions.

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“…Repetitive DNA sequences can form unusual secondary structures28 to which DNA mismatch repair proteins bind and, in the process of repair, cause somatic instability (often expansion) of the CAG repeats. A number of enzymes with the ability to nick DNA and therefore necessitate DNA repair are known to promote CAG expansion and both somatic expansion and HD‐related phenotypes are ameliorated in mouse models by manipulating genes associated with DNA repair 15, 29, 30, 31, 32.…”

Section: Discussionmentioning

confidence: 99%

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

Bettencourt

Hensman-Moss

Flower

et al. 2016

Annals of Neurology

197

186

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ObjectiveThe polyglutamine diseases, including Huntington's disease (HD) and multiple spinocerebellar ataxias (SCAs), are among the commonest hereditary neurodegenerative diseases. They are caused by expanded CAG tracts, encoding glutamine, in different genes. Longer CAG repeat tracts are associated with earlier ages at onset, but this does not account for all of the difference, and the existence of additional genetic modifying factors has been suggested in these diseases. A recent genome‐wide association study (GWAS) in HD found association between age at onset and genetic variants in DNA repair pathways, and we therefore tested whether the modifying effects of variants in DNA repair genes have wider effects in the polyglutamine diseases.MethodsWe assembled an independent cohort of 1,462 subjects with HD and polyglutamine SCAs, and genotyped single‐nucleotide polymorphisms (SNPs) selected from the most significant hits in the HD study.ResultsIn the analysis of DNA repair genes as a group, we found the most significant association with age at onset when grouping all polyglutamine diseases (HD+SCAs; p = 1.43 × 10–5). In individual SNP analysis, we found significant associations for rs3512 in FAN1 with HD+SCAs (p = 1.52 × 10–5) and all SCAs (p = 2.22 × 10–4) and rs1805323 in PMS2 with HD+SCAs (p = 3.14 × 10–5), all in the same direction as in the HD GWAS.InterpretationWe show that DNA repair genes significantly modify age at onset in HD and SCAs, suggesting a common pathogenic mechanism, which could operate through the observed somatic expansion of repeats that can be modulated by genetic manipulation of DNA repair in disease models. This offers novel therapeutic opportunities in multiple diseases. Ann Neurol 2016;79:983–990

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Expandable DNA repeats and human disease

Cited by 844 publications

References 98 publications

Poly(ADP-Ribosyl) Glycohydrolase Prevents the Accumulation of Unusual Replication Structures during Unperturbed S Phase

Poly(ADP-Ribosyl) Glycohydrolase Prevents the Accumulation of Unusual Replication Structures during Unperturbed S Phase

Unusual structures of TTTA repeats in icaC gene of Staphylococcus aureus

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

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