G-quadruplex recognition and remodeling by the FANCJ helicase

Wu, Colin G.; Spies, Maria

doi:10.1093/nar/gkw574

Cited by 88 publications

(104 citation statements)

References 63 publications

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“…Because the helicase remains anchored at the 3′-ssDNA junction, a loop of ssDNA is created as the helicase reels in the tail as it translocates toward the 3′-end of the DNA. Similar repetitive activity has been observed previously for E. coli Rep [91], E. coli UvrD [92], B. stearothermophilus PcrA [93], S. cerevisiae Srs2 [94], and human FANCJ [95], RHAU [96], WRN [96], and BLM [96,97] helicases. Such an activity could have biological significance in clearing DNA of proteins and secondary structures.…”

Section: Role Of Pif1 In Replication Through Barrierssupporting

confidence: 83%

Structure and function of Pif1 helicase

Byrd

Raney

2017

Biochemical Society Transactions

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Pif1 family helicases have multiple roles in maintenance of nuclear and mitochondrial DNA in eukaryotes. S. cerevisiae Pif1 is involved in replication through barriers to replication such as G-quadruplexes and protein blocks and reduces genetic instability at these sites. Another Pif1 family helicase in S. cerevisiae, Rrm3, assists in fork progression through replication fork barriers at the rDNA locus and tRNA genes. ScPif1 also negatively regulates telomerase, facilitates Okazaki Fragment processing, and acts with polymerase δ in break induced repair. Recent crystal structures of bacterial Pif1 helicases and the helicase domain of human PIF1 combined with several biochemical and biological studies on the activities of Pif1 helicases have increased our understanding of the function of these proteins. This review article focuses on these structures and the mechanism(s) proposed for Pif1’s various activities on DNA.

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Section: Role Of Pif1 In Replication Through Barrierssupporting

confidence: 83%

Structure and function of Pif1 helicase

Byrd

Raney

2017

Biochemical Society Transactions

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“…Along with DHX36, two of these helicases are targeted to G4s by binding through a distinct site. BLM, a RecQ family helicase, binds through its HRDC domain (47), while FANCJ binds through a sequence that is related to a key sequence within the Nterminal domain of DHX36 (48). Despite these similarities, our work now sets DHX36 apart by showing that it disrupts a G4 ~1000-fold more efficiently than a duplex of comparable stability.…”

Section: Discussionmentioning

confidence: 85%

The G-quadruplex (G4) resolvase DHX36 efficiently and specifically disrupts DNA G4s via a translocation-based helicase mechanism

Yangyuoru

Bradburn

et al. 2018

Journal of Biological Chemistry

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Single-stranded DNA (ssDNA) and RNA regions that include at least four closely spaced runs of three or more consecutive guanosines strongly tend to fold into stable G-quadruplexes (G4s). G4s play key roles as DNA regulatory sites and as kinetic traps that can inhibit biological processes, but how G4s are regulated in cells remains largely unknown. Here, we developed a kinetic framework for G4 disruption by DEAH-box helicase 36 (DHX36), the dominant G4 resolvase in human cells. Using tetramolecular DNA and RNA G4s with four to six G-quartets, we found that DHX36-mediated disruption is highly efficient, with rates that depend on G4 length under saturating conditions (k cat ) but not under subsaturating conditions (k cat /K M ). These results suggest that a step during G4 disruption limits the k cat value and that DHX36 binding limits k cat /K M . Similar results were obtained for unimolecular DNA G4s. DHX36 activity depended on a 3′ ssDNA extension and was blocked by a polyethylene glycol linker, indicating that DHX36 loads onto the extension and translocates 3′-5′ toward the G4. DHX36 unwound dsDNA poorly compared with G4s of comparable intrinsic lifetime. Interestingly, we observed that DHX36 has striking 3′-extension sequence preferences that differ for G4 disruption and dsDNA unwinding, most likely arising from differences in the rate-limiting step for the two activities. Our results indicate that DHX36 disrupts G4s with a conventional helicase mechanism that is tuned for great efficiency and specificity for G4s. The dependence of DHX36 on the 3′-extension sequence suggests that the extent of formation of genomic G4s may not track directly with G4 stability. ___________________________________Single-stranded DNA and RNA segments that include at least four closely-spaced runs of three or more consecutive guanosine nucleotides have a strong intrinsic propensity to fold into stable G-quadruplex structures (G4s) (1) (Fig. 1A, top left). The genomes of humans and many other eukaryotes are replete with putative G4-forming sequences, and pronounced, conserved patterns have been observed in their distribution, suggesting that Gquadruplex structures form at least transiently in cells and perform conserved functions (2-6). Supporting this hypothesis, G4s have been detected in cells for both .To function as regulatory elements, G4s must be folded and disrupted in a regulated way. In addition, processes that require single-stranded DNA or RNA, such as replication and translation, require that G4s be temporarily disrupted. The high stability and long intrinsic lifetime of G4s suggest Mechanism of G4 disruption by DHX362 that their efficient disruption requires the activity of ATP-dependent enzymes such as helicases.Supporting this view, incorporation of sequences predicted to form particularly stable G4s leads to genetic instability in yeast, suggesting that these G4 structures are not processed efficiently and pose blocks to replication (12). Indeed, several helicases have been shown to possess G4 disruption acti...

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“…Sale and co‐workers confirmed that WRN and BLM contributed to counteracting replication fork stalling at G4s in avian cells and showed that FANCJ, another G4‐unwinding helicase, coordinated this process. The role of FANCJ in the maintenance of chromatin structure near G4‐prone sites was further characterized in works from 2013 to 2016 . Subsequent studies have revealed additional factors that assist in overcoming the G4 replication barrier, including the PrimPol DNA polymerase/primase …”

Section: Persistent G4s Hinder Replication and Uncouple Dna Synthesismentioning

confidence: 99%

DNA G‐Quadruplexes (G4s) Modulate Epigenetic (Re)Programming and Chromatin Remodeling

2019

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Here, the emerging data on DNA G‐quadruplexes (G4s) as epigenetic modulators are reviewed and integrated. This concept has appeared and evolved substantially in recent years. First, persistent G4s (e.g., those stabilized by exogenous ligands) were linked to the loss of the histone code. More recently, transient G4s (i.e., those formed upon replication or transcription and unfolded rapidly by helicases) were implicated in CpG island methylation maintenance and de novo CpG methylation control. The most recent data indicate that there are direct interactions between G4s and chromatin remodeling factors. Finally, multiple findings support the indirect participation of G4s in chromatin reshaping via interactions with remodeling‐related transcription factors (TFs) or damage responders. Here, the links between the above processes are analyzed; also, how further elucidation of these processes may stimulate the progress of epigenetic therapy is discussed, and the remaining open questions are highlighted.

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G-quadruplex recognition and remodeling by the FANCJ helicase

Cited by 88 publications

References 63 publications

Structure and function of Pif1 helicase

Structure and function of Pif1 helicase

The G-quadruplex (G4) resolvase DHX36 efficiently and specifically disrupts DNA G4s via a translocation-based helicase mechanism

DNA G‐Quadruplexes (G4s) Modulate Epigenetic (Re)Programming and Chromatin Remodeling

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