A Distinct Triplex DNA Unwinding Activity of ChlR1 Helicase

Guo, Mingke; Hundseth, Kristian; Ding, Hao; Vidhyasagar, Venkatasubramanian; Inoue, Akira; Nguyen, Chi-Hung; Zain, Rula; Lee, Jeremy S.; Wu, Yuliang

doi:10.1074/jbc.m114.634923

Cited by 52 publications

(52 citation statements)

References 69 publications

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“…In vitro studies have demonstrated that different DNA helicases, such as RecQ [Bacolla et al., ], DHX9 [Jain et al., ], and ChlR1 [Guo et al., ], are able to resolve triplex DNA structures [León‐Ortiz et al., ], and that the lack of these activities is generally associated with genomic instability [Bacolla et al., ; Jain et al., ; Guo et al., ]. Thus, it is possible that DNA helicase activity might also contribute to the processing of R•Y‐rich mirror repeats following an initial single strand break.…”

Section: Resultsmentioning

confidence: 99%

A Role for Non-B DNA Forming Sequences in Mediating Microlesions Causing Human Inherited Disease

et al. 2015

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Missense/nonsense mutations and micro-deletions/micro-insertions of <21bp together represent ~76% of all mutations causing human inherited disease. Previous studies have shown that their occurrence is influenced by sequences capable of non-B DNA formation (direct, inverted and mirror repeats; G-quartets). We found that a greater than expected proportion (~21%) of both micro-deletions and micro-insertions occur within direct repeats and are explicable by slipped misalignment. A novel mutational mechanism, non-B DNA triplex formation followed by DNA repair, is proposed to explain ~5% of micro-deletions and microinsertions at mirror repeats. Further, G-quadruplex-forming sequences, direct and inverted repeats appear to play a prominent role in mediating missense mutations, whereas only direct and inverted repeats mediate nonsense mutations. We suggest a mutational mechanism involving slipped strand mispairing, slipped structure formation and DNA repair, to explain ~15% of missense and ~12% of nonsense mutations leading to the formation of perfect direct repeats from imperfect repeats, or to the extension of existing direct repeats. Similar proportions of missense and nonsense mutations were explicable by the mechanism of hairpin loop formation and DNA repair leading to the formation of perfect inverted repeats from imperfect repeats. The proposed mechanisms provide new insights into mutagenesis underlying pathogenic micro-lesions.

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Section: Resultsmentioning

confidence: 99%

A Role for Non-B DNA Forming Sequences in Mediating Microlesions Causing Human Inherited Disease

et al. 2015

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“…As noted above, Timeless interacts with DDX11 29,36,50 , and this interaction has been shown to be important for sister chromatid cohesion 50 and preservation of fork progression in perturbed conditions 36 . Further, in vitro, DDX11 can unwind several DNA structures including G4s [38][39][40] and the activity of DDX11 is stimulated by Timeless 36 . Recent work has shown that DDX11 interacts with Timeless through a domain in exon 4 50 .…”

Section: Ddx11 Ensures Processive G4 Replication In Vivomentioning

confidence: 99%

Timeless couples G quadruplex detection with processing by DDX11 during DNA replication

Lerner

Holzer

Kilkenny

et al. 2019

Preprint

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& equal contribution2 Regions of the genome with the potential to form secondary structure pose a frequent and significant impediment to DNA replication and must be actively managed in order to preserve genetic and epigenetic integrity. The fork protection complex (FPC), a conserved group of replisome-associated proteins including Timeless, Tipin, and Claspin, plays an important role in maintaining efficient replisome activation, ensuring optimum fork rates, sister chromatid cohesion and checkpoint function. It also helps maintain the stability of sequences prone to secondary structure formation through an incompletely understood mechanism. Here, we report a previously unappreciated DNA binding domain in the C-terminus of Timeless, which exhibits specific binding to G quadruplex (G4) structures. We show that, in vivo, both the C-terminus of Timeless and the DDX11 helicase act collaboratively to ensure processive replication of G4 structures to prevent genetic and epigenetic instability.DNA can create significant impediments to its own replication through formation of secondary structures. When unwound, certain sequences, often repetitive or of low complexity, can adopt a variety of non-B form structures, including hairpins, cruciforms, triplexes and quadruplexes 1 . It is becoming clear that secondary structure formation is a frequent event during replication, even at genomically abundant sequences previously thought not to be a major source of difficulty 2 . To prevent such sequences causing havoc with the genetic and epigenetic stability of the genome, cells deploy an intricate network of activities to counteract secondary structure formation and limit its effects. These activities include proteins that bind and destabilise DNA structures and specialised helicases that unwind them 3 . In addition, the repriming activity of PrimPol can be deployed to confine a structure into a minimal region of single stranded DNA, limiting the potential dangers of exposing extensive ssDNA in a stalled replisome 2,4 . G quadruplexes (G4s) are one of the most intensively studied and potent structural replication impediments. G4s arise in consequence of the ability of guanine to form Hoogsteen base-paired quartets 5 . In favourable sequence contexts, comprising runs of dG separated by variable numbers of non-G bases, stacks of G quartets form G4s secondary structures. Current estimates suggest that over 700,000 sites in the human genome have the potential to form G4s 6 . While some of these G4s may have important roles in genome physiology, all pose a potential threat to DNA replication and sites with G4-forming potential have been linked to both genetic and epigenetic instability 7,8 .3Precisely how DNA structures are detected and resolved by the replication machinery remains unclear. Many of the factors involved in processing G4 secondary structures, for instance FANCJ and REV1 9-13 , do not appear to be constitutive components of the replisome 14 . It is thus likely that core components of the replisome will act as 'first respo...

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“…Triplex-unwinding helicases, on the other hand, are still largely unknown. Reports have demonstrated in vitro triplex-unwinding activity for several proteins, namely human Dhx9 (358), Ddx11 (359), and BLM and WRN helicases (360) as well as the yeast Stm1 protein (361). However, in vivo evidence for the involvement of these helicases in triplex unwinding is scarce.…”

Section: How To Maintain Hard-to-replicate Expandable Repeats?mentioning

confidence: 99%

On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability

Khristich

Mirkin

2020

Journal of Biological Chemistry

232

239

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Expansions of simple tandem repeats are responsible for almost 50 human diseases, the majority of which are severe, degenerative, and not currently treatable or preventable. In this review, we first describe the molecular mechanisms of repeat-induced toxicity, which is the connecting link between repeat expansions and pathology. We then survey alternative DNA structures that are formed by expandable repeats and review the evidence that formation of these structures is at the core of repeat instability. Next, we describe the consequences of the presence of long structure-forming repeats at the molecular level: somatic and intergenerational instability, fragility, and repeat-induced mutagenesis. We discuss the reasons for gender bias in intergenerational repeat instability and the tissue specificity of somatic repeat instability. We also review the known pathways in which DNA replication, transcription, DNA repair, and chromatin state interact and thereby promote repeat instability. We then discuss possible reasons for the persistence of disease-causing DNA repeats in the genome. We describe evidence suggesting that these repeats are a payoff for the advantages of having abundant simple-sequence repeats for eukaryotic genome function and evolvability. Finally, we discuss two unresolved fundamental questions: (i) why does repeat behavior differ between model systems and human pedigrees, and (ii) can we use current knowledge on repeat instability mechanisms to cure repeat expansion diseases?

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A Distinct Triplex DNA Unwinding Activity of ChlR1 Helicase

Cited by 52 publications

References 69 publications

A Role for Non-B DNA Forming Sequences in Mediating Microlesions Causing Human Inherited Disease

A Role for Non-B DNA Forming Sequences in Mediating Microlesions Causing Human Inherited Disease

Timeless couples G quadruplex detection with processing by DDX11 during DNA replication

On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability

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