Levitus, M. et al. The DNA helicase BRIP1 is defective in Fanconi anemia complementation group J. Nature Genet. 37, 934-935

Department of Clinical Genetics and Human Genetics, VU University Medical Center, Van der Boechorststraat 7, NL-1081 BT Amsterdam, The Netherlands.
Nature Genetics (Impact Factor: 29.35). 10/2005; 37(9):934-5. DOI: 10.1038/ng1625
Source: PubMed


The protein predicted to be defective in individuals with Fanconi anemia complementation group J (FA-J), FANCJ, is a missing component in the Fanconi anemia pathway of genome maintenance. Here we identify pathogenic mutations in eight individuals with FA-J in the gene encoding the DEAH-box DNA helicase BRIP1, also called FANCJ. This finding is compelling evidence that the Fanconi anemia pathway functions through a direct physical interaction with DNA.

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Available from: Kevin Hiom, Mar 13, 2014
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    • "More recently , a significant association with pancreatic and colorectal cancer was found (Rafnar et al. 2011). In line with its role in the FA pathway, defects in FANCJ give rise to exquisite ICL sensitivity in a range of different species (Bridge et al. 2005; Levitus et al. 2005; Litman et al. 2005; Youds et al. 2008). However, attempts to place FANCJ within the FA pathway have provided little insight into its precise function in ICL repair. "
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    ABSTRACT: Microsatellites are short tandem repeat sequences that are highly prone to expansion/contraction due to their propensity to form non-B-form DNA structures, which hinder DNA polymerases and provoke template slippage. Although error correction by mismatch repair plays a key role in preventing microsatellite instability (MSI), which is a hallmark of Lynch syndrome, activities must also exist that unwind secondary structures to facilitate replication fidelity. Here, we report that Fancj helicase-deficient mice, while phenotypically resembling Fanconi anemia (FA), are also hypersensitive to replication inhibitors and predisposed to lymphoma. Whereas metabolism of G4-DNA structures is largely unaffected in Fancj−/− mice, high levels of spontaneous MSI occur, which is exacerbated by replication inhibition. In contrast, MSI is not observed in Fancd2−/− mice but is prevalent in human FA-J patients. Together, these data implicate FANCJ as a key factor required to counteract MSI, which is functionally distinct from its role in the FA pathway.
    Full-text · Article · Dec 2015 · Genes & Development
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    • "The vertebrate homologue of DOG-1 is FANCJ, also named BACH1 or BRIP1, which performs several roles in genome maintenance . FANCJ is one of the 16 genes that, when mutated, cause Fanconi anemia (FA); a human cancer-predisposition disorder characterized by cellular sensitivity to DNA interstrand crosslinking agents (Levitus et al, 2005; Levran et al, 2005; Muniandy et al, 2010). In addition to its function in interstrand crosslink repair, FANCJ has also been suggested to play a role in the processing of G-quadruplex structures, primarily based on the G4 sequence instability phenotype of DOG-1/FANCJ deficient C. elegans strains. "
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    ABSTRACT: Our genome contains many G-rich sequences, which have the propensity to fold into stable secondary DNA structures called G4 or G-quadruplex structures. These structures have been implicated in cellular processes such as gene regulation and telomere maintenance. However, G4 sequences are prone to mutations particularly upon replication stress or in the absence of specific helicases. To investigate how G-quadruplex structures are resolved during DNA replication, we developed a model system using ssDNA templates and Xenopus egg extracts that recapitulates eukaryotic G4 replication. Here, we show that G-quadruplex structures form a barrier for DNA replication. Nascent strand synthesis is blocked at one or two nucleotides from the G4. After transient stalling, G-quadruplexes are efficiently unwound and replicated. In contrast, depletion of the FANCJ/BRIP1 helicase causes persistent replication stalling at G-quadruplex structures, demonstrating a vital role for this helicase in resolving these structures. FANCJ performs this function independently of the classical Fanconi anemia pathway. These data provide evidence that the G4 sequence instability in FANCJ−/− cells and Fancj/dog1 deficient C. elegans is caused by replication stalling at G-quadruplexes.
    Full-text · Article · Sep 2014 · The EMBO Journal
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    • "DDX11 shares sequence homology with the related SF2 DNA helicases FANCJ (MIM# 609054), ERCC2 (XPD; MIM# 126340), and RTEL1 (MIM# 608833), which all contain an iron–sulfur (Fe–S) motif between helicase domains IA and II [Rudolf et al., 2006; Wu et al., 2009]. FANCJ and ERCC2 (also known as XPD) are also implicated with genetic instability disorders in humans, and RTEL1 had been suggested to play a role in the maintenance of telomere length and genome stability in mice [Ding et al., 2004; Lehmann, 2001; Levitus et al., 2005]. "
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    ABSTRACT: Mutations in the gene encoding the iron-sulfur-containing DNA helicase DDX11 (ChlR1) were recently identified as a cause of a new recessive cohesinopathy, Warsaw breakage syndrome (WABS), in a single patient with severe microcephaly, pre- and postnatal growth retardation, and abnormal skin pigmentation. Here, using homozygosity mapping in a Lebanese consanguineous family followed by exome sequencing, we identified a novel homozygous mutation (c.788G>A [p.R263Q]) in DDX11 in three affected siblings with severe intellectual disability and many of the congenital abnormalities reported in the WABS original case. Cultured lymphocytes from the patients showed increased mitomycin C-induced chromosomal breakage, as found in WABS. Biochemical studies of purified recombinant DDX11 indicated that the p.R263Q mutation impaired DDX11 helicase activity by perturbing its DNA binding and DNA-dependent ATP hydrolysis. Our findings thus confirm the involvement of DDX11 in WABS, describe its phenotypical spectrum, and provide novel insight into the structural requirement for DDX11 activity.
    Full-text · Article · Jan 2013 · Human Mutation
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