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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    • "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.
    The EMBO Journal 09/2014; 33(21). DOI:10.15252/embj.201488663 · 10.43 Impact Factor
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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.
    Human Mutation 01/2013; 34(1). DOI:10.1002/humu.22226 · 5.14 Impact Factor
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    • "Mutations in FANCJ have been reported to be associated with an increased risk of breast and ovarian cancer (Cantor et al. 2001; Rutter et al. 2003; Seal et al. 2006; Rafnar et al. 2011). FANCJ is one of the 15 Fanconi anemia genes, in which cells are hypersensitive to DNA-cross-linking agents (Levitus et al. 2005; Levran et al. 2005; Litman et al. 2005). FANCJ has been reported to contribute to DSB repair mediated by HR and S-phase checkpoint activation (Cantor et al. 2001; Bridge et al. 2005; Litman et al. 2005; Greenberg et al. 2006), although the absolute underlying mechanism remains unclear. "
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    ABSTRACT: FANCJ, also called BACH1/BRIP1, is a 5'-3' DEAH helicase, whose mutations are known as a risk factor for Fanconi anemia and also breast and ovarian cancer. FANCJ is thought to contribute to DNA double-strand break (DSB) repair and S-phase checkpoint through binding to multiple partner proteins, such as BRCA1 and TopBP1, but its molecular regulation remains unclear. We focused on DNA damage-induced phosphorylation of FANCJ and found that reagents that cause DSB or replication fork stalling induce FANCJ hyperphosphorylation. In particular, camptothecin (CPT) induced rapid and efficient FANCJ hyperphosphorylation that was largely dependent on TopBP1 and ATM-Rad3 related (ATR) kinase. Furthermore, DNA end resection that exposes single-strand DNA at the DSB site was required for hyperphosphorylation. Interestingly, upon CPT treatment, a dramatic increase in the FANCJ-TopBP1 complex was observed, and this increase was not alleviated even when ATR-dependent hyperphosphorylation was suppressed. These results suggest that FANCJ function may be modulated by hyperphosphorylation in a DNA end resection- and ATR-dependent manner and by FANCJ-TopBP1 complex formation in response to replication-coupled DSBs.
    Genes to Cells 11/2012; 17(12). DOI:10.1111/gtc.12011 · 2.81 Impact Factor
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