FANCJ suppresses microsatellite instability and lymphomagenesis independent of the Fanconi anemia pathway

Matsuzaki, Kei; Borel, Valérie; Adelman, Carrie A.; Schindler, Detlev; Boulton, Simon J.

doi:10.1101/gad.272740.115

Cited by 53 publications

(66 citation statements)

References 51 publications

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“…In a system used to detect gross chromosomal rearrangements due to G4 DNA Pif1 was shown to be important in preventing genomic instability, suggesting that Pif1-mediated unwinding of G4 DNA prevents error-prone replication or repair (60). Another helicase involved in TNR instability in mammalian cells is the 5′-3′ helicase FANCJ, a member of the Fanconia Anemia pathway, which can unwind G4 DNA and CAG/CTG hairpins during replication to prevent repeat instability (61, 62). Unwinding non-B form DNA structures to prevent instability is a unique role for FANCJ as other members of the Fanconi Anemia (FA) pathway did not exhibit similar roles (62).…”

Section: Recombination During Replication Results In Repeat Instabilitymentioning

confidence: 99%

Role of recombination and replication fork restart in repeat instability

2017

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Eukaryotic genomes contain many repetitive DNA sequences that exhibit size instability. Some repeat elements have the added complication of being able to form secondary structures, such as hairpin loops, slipped DNA, triplex DNA or G-quadruplexes. Especially when repeat sequences are long, these DNA structures can form a significant impediment to DNA replication and repair, leading to DNA nicks, gaps, and breaks. In turn, repair or replication fork restart attempts within the repeat DNA can lead to addition or removal of repeat elements, which can sometimes lead to disease. One important DNA repair mechanism to maintain genomic integrity is recombination. Though early studies dismissed recombination as a mechanism driving repeat expansion and instability, recent results indicate that mitotic recombination is a key pathway operating within repetitive DNA. The action is two-fold: first, it is an important mechanism to repair nicks, gaps, breaks, or stalled forks to prevent chromosome fragility and protect cell health; second, recombination can cause repeat expansions or contractions, which can be deleterious. In this review, we summarize recent developments that illuminate the role of recombination in maintaining genome stability at DNA repeats.

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Section: Recombination During Replication Results In Repeat Instabilitymentioning

confidence: 99%

Role of recombination and replication fork restart in repeat instability

2017

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“…This RPA binding domain (RBD) shares sequence similarity to many other proteins that interact with RPA32, including DNA damage response proteins like ETAA1 and nucleotide excision repair protein XPA (Matsuzaki et al , 2015, Bass et al , 2016, Haahr et al , 2016). As many proteins bind the same surface on RPA, it is important to understand how these interactions are coordinated to permit rapid repair of DNA damage.…”

Section: Smarcal1mentioning

confidence: 99%

Functions of SMARCAL1, ZRANB3, and HLTF in maintaining genome stability

Poole

Chen

2017

Critical Reviews in Biochemistry and Molecular Biology

124

104

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A large number of SNF2 family, DNA and ATP-dependent motor proteins are needed during transcription, DNA replication, and DNA repair to manipulate protein-DNA interactions and change DNA structure. SMARCAL1, ZRANB3, and HLTF are three related members of this family with specialized functions that maintain genome stability during DNA replication. These proteins are recruited to replication forks through protein-protein interactions and bind DNA using both their motor and substrate recognition domains (SRD). The SRD provides specificity to DNA structures like forks and junctions and confer DNA remodeling activity to the motor domains. Remodeling reactions include fork reversal and branch migration to promote fork stabilization, template switching, and repair. Regulation ensures these powerful activities remain controlled and restricted to damaged replication forks. Inherited mutations in SMARCAL1 cause a severe developmental disorder and mutations in ZRANB3 and HLTF are linked to cancer illustrating the importance of these enzymes in ensuring complete and accurate DNA replication. In this review, we examine how these proteins function, concentrating on their common and unique attributes and regulatory mechanisms.

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“…G quadruplexes have been observed to form in human cells [115] and human cells in which mutant FANCJ protein is deficient in G quadruplex unwinding accumulate deletions at or near G quadruplex consensus sequences [105]. FANCJ patient cells are hypersensitive to interstrand crosslinking reagents such as mitomycin C (MMC) and other DNA polymerase inhibitors, supporting a direct role for FANCJ in stabilization of DNA replication forks [106,117–122]. Moreover, mutation of the C. elegans dog-1 helicase results in loss of DNA sequences flanking long runs of guanines [107,108].…”

Section: Microsatellite Repeats Are Sites Of Genome Stressmentioning

confidence: 99%

Replication stalling and DNA microsatellite instability

Gadgil

Barthelemy

Lewis

et al. 2017

Biophysical Chemistry

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Microsatellites are short, tandemly repeated DNA motifs of 1–6 nucleotides, also termed simple sequence repeats (SRSs) or short tandem repeats (STRs). Collectively, these repeats comprise approximately 3% of the human genome Subramanian et al. (2003), Lander and Lander (2001) [1,2], and represent a large reservoir of loci highly prone to mutations Sun et al. (2012), Ellegren (2004) [3,4] that contribute to human evolution and disease. Microsatellites are known to stall and reverse replication forks in model systems Pelletier et al. (2003), Samadashwily et al. (1997), Kerrest et al. (2009) [5–7], and are hotspots of chromosomal double strand breaks (DSBs). We briefly review the relationship of these repeated sequences to replication stalling and genome instability, and present recent data on the impact of replication stress on DNA fragility at microsatellites in vivo.

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FANCJ suppresses microsatellite instability and lymphomagenesis independent of the Fanconi anemia pathway

Cited by 53 publications

References 51 publications

Role of recombination and replication fork restart in repeat instability

Role of recombination and replication fork restart in repeat instability

Functions of SMARCAL1, ZRANB3, and HLTF in maintaining genome stability

Replication stalling and DNA microsatellite instability

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