Article

Assessing the link between BACH1 and BRCA1 in the FA pathway

Department of Cancer Biology, University of Massachusetts Medical School, Women's Cancers Program, UMASS Memorial Cancer Center, Worcester, Massachusetts 01605, USA.
Cell cycle (Georgetown, Tex.) (Impact Factor: 4.57). 02/2006; 5(2):164-7. DOI: 10.4161/cc.5.2.2338
Source: PubMed

ABSTRACT

The BACH1 helicase was initially identified by its direct binding to BRCA1 and, thus, was linked to hereditary breast cancer. More recently, BACH1 was identified as the gene defective in the J complementation group of Fanconi anemia (FA). FA is a multigenetic disorder characterized by cellular sensitivity to crosslinkers and chromosome instability. Because FANCD2 monoubiquitination is intact in BACH1 deficient cells, BACH1 appears to act downstream in the FA pathway akin to BRCA2/FANCD1. Interestingly, while BRCA1 has various interactions with FA proteins it has not been identified as an FA gene. As the race to uncover the last few unknown FA complementation groups comes to an end, future work will be required to uncover how these gene products function to combat the effects of DNA damage and maintain genomic stability. In particular, it remains elusive whether BRCA1 is functionally linked to the FA pathway through its interaction with BACH1/FANCJ. This review focuses on a model for the connection of BRCA1 to BACH1 in the FA pathway. We predict that BRCA1 regulates the BACH1 helicase activity to coordinate the timely displacement of Rad51 from nucleofilaments, promoting error free repair and ultimately maintaining chromosomal integrity.

Download full-text

Full-text

Available from: Sharon B Cantor, Jan 09, 2014
  • Source
    • "An extensive database points to the multiple links of the FANCJ (FANCJ/BACH1/BRIP1) protein with OS (Table 4). This protein displays functional interaction with BRCA1 in breast and ovary cancer suppression and DNA repair [47] [48] and, in turn, BRCA1 is known to be involved in OS-related mechanisms [49]. Moreover, FANCJ/BACH1/BRIP1 competes with Nrf2, leading to negative regulation of the antioxidant-response element-mediated NAD(P)H:quinone oxidoreductase 1 gene expression and induction in response to antioxidants [50], and features a helicase activity and an ATPase activity, a twofold activity that is recognized for other RECQ helicases that are associated with ATPase activity [51]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Fanconi anaemia (FA) is a rare genetic disease associated to deficiencies in DNA repair pathways. A body of literature points to a prooxidant state in FA patients, along with the evidence for oxidative stress (OS) in FA phenotype reported by in vitro, molecular and animal studies. A highlight arises from the detection of mitochondrial dysfunction (MDF) in FA cell lines of complementation groups A, C, D2 and G. As yet lacking, in vivo studies should focus on FA-associated MDF that may help understanding the mitochondrial basis of OS detected in cells and body fluids from FA patients. Beyond the in vitro and animal database, the available analytical devices may prompt the direct observation of metabolic and mitochondrial alterations in FA patients. These studies should evaluate a set of MDF-related endpoints, to be related with OS endpoints. The working hypothesis is raised that, parallel to OS, nitrosative stress might be another, so far unexplored hallmark of FA phenotype. The expected results may shed light into FA pathogenesis and might provide the grounds for pilot chemoprevention trials using mitochondrial nutrients.
    Full-text · Article · Jan 2013 · Free Radical Biology and Medicine
  • Source
    • "An extensive database points to the multiple links of the FANCJ (FANCJ/BACH1/BRIP1) protein with OS (Table 4). This protein displays functional interaction with BRCA1 in breast and ovary cancer suppression and DNA repair [47] [48] and, in turn, BRCA1 is known to be involved in OS-related mechanisms [49]. Moreover, FANCJ/BACH1/BRIP1 competes with Nrf2, leading to negative regulation of the antioxidant-response element-mediated NAD(P)H:quinone oxidoreductase 1 gene expression and induction in response to antioxidants [50], and features a helicase activity and an ATPase activity, a twofold activity that is recognized for other RECQ helicases that are associated with ATPase activity [51]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cited By (since 1996):4, Export Date: 18 October 2014
    Full-text · Article · Jan 2013
  • Source
    • "The FANCJ protein was recognized to coincide with two previously known BRCA1-interacting entities, the DNA helicase BRIP1 (BRCA1-interacting protein 1) (Levitus et al. , 2005 ; Levran et al. , 2005 ) and the transcription factor BACH1 (BRCA1-associated C-terminal helicase) (Litman et al. , 2005 ; Cantor and Andreassen , 2006 ). This protein, currently noted as FANCJ/BACH1/BRIP1, displays functional interaction with BRCA1 in breast and ovary cancer suppression and DNA repair (Cantor et al. , 2001, 2004 ; Xie et al. , 2010 ). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Fanconi anaemia (FA) is a genetic disease featuring bone marrow failure, proneness to malignancies, and chromosomal instability. A line of studies has related FA to oxidative stress (OS). This review attempts to evaluate the evidence for FA-associated redox abnormalities in the literature from 1981 to 2010. Among 2170 journal articles on FA evaluated, 162 related FA with OS. Early studies reported excess oxygen toxicity in FA cells that accumulated oxidative DNA damage. Prooxidant states were found in white blood cells and body fluids from FA patients as excess luminol-dependent chemiluminescence, 8-hydroxy-deoxyguanosine, reduced glutathione/oxidized glutathione imbalance, and tumour necrosis factor-α. Some FA gene products involved in redox homeostasis can be summarized as follows: (a) FANCA, FANCC, and FANCG interact with cytochrome P450-related activities and/or respond to oxidative damage; (b) FANCD2 in OS response interacts with forkhead box O3 and ataxia telangiectasia mutated protein; (c) FANCG is found in mitochondria and interacts with PRDX3, and FA-G cells display distorted mitochondria and decreased peroxidase activity; (d) FANCJ (BACH1/BRIP1) is a repressor of haeme oxygenase-1 gene and senses oxidative base damage; (e) antioxidants, such as tempol and resveratrol decrease cancer incidence and haematopoietic defects in Fancd2(-/-) mice. The overall evidence for FA-associated OS may suggest designing chemoprevention studies aimed at delaying the onset of OS-related clinical complications.
    Full-text · Article · Jan 2012 · Biological Chemistry
Show more