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Cited by 106DNA Repair MechanismsBRCA gene mutations in cancerPARP inhibition in cancer therapy

Hereditary Breast Cancer and the BRCA1-Associated FANCJ/BACH1/BRIP1

Open access
Cantor, Sharon B, Guillemette, Shawna·2011·Future Oncology
DOI 10.2217/fon.10.191PMC PMC3109611
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Abstract

It is clear that FANCJ, also known as BACH1 or BRIP1, is an essential tumor suppressor gene based on the identification of clinically relevant mutations not only in breast cancer, but also the childhood cancer syndrome, Fanconi anemia. This conclusion is further supported by the direct and functional interaction between FANCJ and the hereditary breast cancer-associated gene product BRCA1. In the absence of the FANCJ DNA helicase or its interaction with BRCA1, cells have defects in several aspects of the DNA damage response. In particular, the BRCA1-FANCJ interaction is essential for promoting error-free repair, checkpoint control and for limiting DNA damage tolerance. As the number of FANCJ clinical mutations and affected patients accumulate, it will be critical to understand whether the associated tumors resemble BRCA-associated tumors. If so, FANCJ patients could also benefit from new therapies that selectively sensitize DNA repair-defective tumors and spare healthy cells. In this article, we summarize the breast cancer-associated FANCJ mutations and discuss functional outcomes for DNA repair and tumor suppression.

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Crossref · 10.2217/fon.10.191

Cites

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Claims the paper makes

0 of 129 cited sources checked · 0 supported · 0 flagged

  • Findingreasoning

    Breast cancer patients and Fanconi anemia patients have been found to carry FANCJ mutations that disrupt helicase activity.

    “the identification of both breast cancer and FA patients with FANCJ helicase-disrupting mutations”
    Quote in the paperSubstantial claim
  • Findingcitation

    The P47A FANCJ mutant has disrupted enzyme activity.

    “The P47A mutant had disrupted enzyme activity”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [56] Cantor S Drapkin R Zhang F The BRCA1-associated protein BACH1 is a DNA helicase targeted by clinically relevant inactivating mutations Proc. Natl Acad. Sci. USA 2004 101 8 2357 2362 14983014 PMC356955 ▪ First study to demonstrate that mutations identified in breast cancer patients alter FANCJ function in vitro. source

      Not checked in the free run.

    • cites [61] Gupta R Sharma S Sommers JA Jin Z Cantor SB Brosh RM Jr Analysis of the DNA substrate specificity of the human BACH1 helicase associated with breast cancer J. Biol. Chem 2005 280 27 25450 25460 15878853 ▪ Comprehensive characterization of the enzyme activity of FANCJ. source

      Not checked in the free run.

  • Findingcitation

    Cells expressing the BRCA1 interaction-defective FANCJ mutant S990A show reduced DNA repair, similar to cells with the enzyme-inactivating FANCJ mutant K52R.

    “Cells expressing the BRCA1 interaction- defective mutant S990A had reduced DNA repair, similar to an enzyme-inactivating FANCJ mutant, K52R.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [69] Xie J Litman R Wang S Targeting the FANCJ–BRCA1 interaction promotes a switch from recombination to poleta-dependent bypass Oncogene 2010 29 17 2499 2508 20173781 PMC2909592 ▪ Demonstrates that BRCA1 binding to FANCJ in human cells is essential for regulating the choice for DNA repair processing. source

      Not checked in the free run.

  • Findingcitation

    Loss of FANCJ binding to BRCA1 enhances DNA damage tolerance.

    “loss of FANCJ binding to BRCA1 also enhanced DNA damage tolerance [69]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [69] Xie J Litman R Wang S Targeting the FANCJ–BRCA1 interaction promotes a switch from recombination to poleta-dependent bypass Oncogene 2010 29 17 2499 2508 20173781 PMC2909592 ▪ Demonstrates that BRCA1 binding to FANCJ in human cells is essential for regulating the choice for DNA repair processing. source

      Not checked in the free run.

  • Premisecitation

    BRCA1 and BRCA2 share functions in homologous recombination repair of DNA double-strand breaks.

    “The key to targeted therapy, however, is that BRCA1 and BRCA2 have common functions in DNA double-strand break repair in the subpathway of homologous recombination [2,3].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [2] Liu Y West SC Distinct functions of BRCA1 and BRCA2 in double-strand break repair Breast Cancer Res 2002 4 1 9 13 11879553 PMC138716 source

      Not checked in the free run.

    • cites [3] Venkitaraman AR Cancer susceptibility and the functions of BRCA1 and BRCA2 Cell 2002 108 2 171 182 11832208 source

      Not checked in the free run.

  • May combine two claims. 42
  • Classified as probably not a substantial claim. 16

  • May combine two claims.

    Findingcitation

    The M299I FANCJ mutant has enhanced ATPase, helicase, and translocase activity.

    “the M299I mutant had enhanced ATPase, helicase and translocase activity [56,61]”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [56] Cantor S Drapkin R Zhang F The BRCA1-associated protein BACH1 is a DNA helicase targeted by clinically relevant inactivating mutations Proc. Natl Acad. Sci. USA 2004 101 8 2357 2362 14983014 PMC356955 ▪ First study to demonstrate that mutations identified in breast cancer patients alter FANCJ function in vitro. source

      Not checked in the free run.

    • cites [61] Gupta R Sharma S Sommers JA Jin Z Cantor SB Brosh RM Jr Analysis of the DNA substrate specificity of the human BACH1 helicase associated with breast cancer J. Biol. Chem 2005 280 27 25450 25460 15878853 ▪ Comprehensive characterization of the enzyme activity of FANCJ. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Findingnone given

    The most common germline FANCJ mutant allele, R798x, is found in both breast cancer and Fanconi anemia patients.

    “The most common germline FANCJ mutant allele (R798x) is found in both breast cancer and Fanconi anemia patients.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    FANCJ-deficient cells are sensitive to cisplatin, as are BRCA-deficient cells.

    “similar to BRCA-deficient cells, FANCJ-deficient cells are sensitive to cisplatin [69]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [69] Xie J Litman R Wang S Targeting the FANCJ–BRCA1 interaction promotes a switch from recombination to poleta-dependent bypass Oncogene 2010 29 17 2499 2508 20173781 PMC2909592 ▪ Demonstrates that BRCA1 binding to FANCJ in human cells is essential for regulating the choice for DNA repair processing. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BRCA2 binds and loads RAD51, which mediates strand invasion of duplex DNA with homologous sequences.

    “Subsequently, these DNA ends become competent for recombination when BRCA2 binds and loads RAD51, which mediates strand invasion of duplex DNA with homologous sequences [4].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] Kass EM Jasin M Collaboration and competition between DNA double-strand break repair pathways FEBS Lett 2010 584 17 3703 3708 20691183 PMC3954739 ▪ Reviews double strand break repair pathways and how the choice of pathways is regulated. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The BRCA1-FANCJ interaction is required for error-free repair, checkpoint control, and limiting DNA damage tolerance.

    “In particular, the BRCA1–FANCJ interaction is essential for promoting error-free repair, checkpoint control and for limiting DNA damage tolerance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    CHEK2, ATM, NBS1, RAD50, TOPBP1, and RAD51C are mutated in breast cancer patients.

    “Correspondingly, these and other genes functioning in the DNA damage response, such as CHEK2, ATM, NBS1, RAD50, TOPBP1 and RAD51C, are mutated in breast cancer patients [12–21].”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [12] Meijers-Heijboer H van den Ouweland A Klijn J Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations Nat. Genet 2002 31 1 55 59 11967536 source

      Not checked in the free run.

    • cites [13] Ingvarsson S Sigbjornsdottir BI Huiping C Mutation analysis of the CHK2 gene in breast carcinoma and other cancers Breast Cancer Res 2002 4 3 R4 12052256 PMC111029 source

      Not checked in the free run.

    • cites [14] Sullivan A Yuille M Repellin C Concomitant inactivation of p53 and CHK2 in breast cancer Oncogene 2002 21 9 1316 1324 11857075 source

      Not checked in the free run.

    • cites [15] Allinen M Huusko P Mantyniemi S Launonen V Winqvist R Mutation analysis of the CHK2 gene in families with hereditary breast cancer Br. J. Cancer 2001 85 2 209 212 11461078 PMC2364033 source

      Not checked in the free run.

    • cites [16] Broeks A Urbanus JH Floore AN ATM-heterozygous germline mutations contribute to breast cancer-susceptibility Am. J. Hum. Genet 2000 66 2 494 500 10677309 PMC1288102 source

      Not checked in the free run.

    • cites [17] Brunet J Gutierrez-Enriquez S Torres A ATM germline mutations in Spanish early-onset breast cancer patients negative for BRCA1/BRCA2 mutations Clin. Genet 2008 73 5 465 473 18384426 source

      Not checked in the free run.

    • cites [18] Heikkinen K Rapakko K Karppinen SM RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability Carcinogenesis 2006 27 8 1593 1599 16474176 PMC3006189 source

      Not checked in the free run.

    • cites [19] Going JJ Nixon C Dornan ES Boner W Donaldson MM Morgan IM Aberrant expression of TopBP1 in breast cancer Histopathology 2007 50 4 418 424 17448016 source

      Not checked in the free run.

    • cites [20] Karppinen SM Erkko H Reini K Identification of a common polymorphism in the TopBP1 gene associated with hereditary susceptibility to breast and ovarian cancer Eur. J. Cancer 2006 42 15 2647 2652 16930991 source

      Not checked in the free run.

    • cites [21] Meindl A Hellebrand H Wiek C Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene Nat. Genet 2010 42 15 410 414 20400964 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    People heterozygous for BRCA1 or BRCA2 mutations have a 60-80% lifetime risk of breast cancer.

    “Heterozygous carriers of mutations in the hereditary breast cancer genes BRCA1 or BRCA2 have a 60–80% lifetime risk of breast cancer [1].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Antoniou A Pharoah PD Narod S Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies Am. J. Hum. Genet 2003 72 5 1117 1130 12677558 PMC1180265 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Breast cancer risk in individuals carrying a FANCJ mutation is higher for those with a strong family history.

    “It is worth considering that the breast cancer risk in individuals carrying a FANCJ mutation will be higher for those with a strong family history [55].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Byrnes GB Southey MC Hopper JL Are the so-called low penetrance breast cancer genes, ATM, BRIP1, PALB2 and CHEK2, high risk for women with strong family histories? Breast Cancer Res 2008 10 3 208 18557994 PMC2481495 ▪ Explains how low-penetrance genes affect the risk for families with cancer predisposition. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Hereditary breast cancer arises from defective DNA repair, implying that resulting tumors may be sensitive to therapies effective against BRCA tumors.

    “The emerging picture is that hereditary breast cancer derives from defective DNA repair, with the implication that derived tumors will have sensitivity to current therapies that are effective on BRCA tumors.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Fanconi anemia patient cells are extremely sensitive to agents that induce DNA interstrand crosslinks.

    “FA is a rare cancer-prone disease in which patients’ cells are characterized by extreme sensitivity to agents that induce DNA interstrand crosslinks (for review, see [22,23]).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [22] D’Andrea AD Grompe M The Fanconi anaemia/BRCA pathway Nat. Rev. Cancer 2003 3 1 23 34 12509764 source

      Not checked in the free run.

    • cites [23] Wang W Emergence of a DNA-damage response network consisting of Fanconi anaemia and BRCA proteins Nat. Rev. Genet 2007 8 10 735 748 17768402 ▪ Reveiws the connection between breast cancer and Fanconi anemia (FA) genes. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The P47A variant, shown to disrupt FANCJ enzyme function, was found in controls of a later study and considered unrelated to breast cancer.

    “For example, the P47A variant identified in 2001 [8] and shown to disrupt FANCJ enzyme function [56] was found in the controls of a subsequent study and considered to be unrelated to breast cancer [44].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [8] Cantor SB Bell DW Ganesan S BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function Cell 2001 105 1 149 160 11301010 ▪▪ Describes how FANCJ, originally termed BACH1, was identified as a BRCA1-interacting helicase that is mutated in breast cancer. source

      Not checked in the free run.

    • cites [56] Cantor S Drapkin R Zhang F The BRCA1-associated protein BACH1 is a DNA helicase targeted by clinically relevant inactivating mutations Proc. Natl Acad. Sci. USA 2004 101 8 2357 2362 14983014 PMC356955 ▪ First study to demonstrate that mutations identified in breast cancer patients alter FANCJ function in vitro. source

      Not checked in the free run.

    • cites [44] Seal S Thompson D Renwick A Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles Nat. Genet 2006 38 11 1239 1241 17033622 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The FANCJ gene contains 20 exons spanning more than 180 kb of genomic sequence at chromosome 17q22.

    “The purified 130-kDa protein was subject to tandem mass spectrometry and the FANCJ gene was cloned and found to consist of 20 exons spanning greater than 180 kb of genomic sequence in chromosome 17q22.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Cantor SB Bell DW Ganesan S BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function Cell 2001 105 1 149 160 11301010 ▪▪ Describes how FANCJ, originally termed BACH1, was identified as a BRCA1-interacting helicase that is mutated in breast cancer. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The P47A mutant is enzymatically inactive in vitro, similar to K52R or A349P, which dominantly disrupted DNA repair when expressed in cells.

    “Consistent with this idea, the P47A mutant is enzyme inactive in vitro, similar to the helicace-inactive FANCJ mutant species, K52R, or FA-associated A349P, which dominantly disrupted DNA repair when expressed in cells [41,42].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [41] Cantor SB Xie J Assessing the link between BACH1/FANCJ and MLH1 in DNA crosslink repair Environ. Mol. Mutagen 2010 51 6 500 507 20658644 source

      Not checked in the free run.

    • cites [42] Wu Y Sommers JA Suhasini AN Fanconi anemia group J mutation abolishes its DNA repair function by uncoupling DNA translocation from helicase activity or disruption of protein–DNA complexes Blood 2010 116 19 3780 3791 20639400 PMC2981534 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A breast cancer cell line expressing truncated BRCA1 lacking functional BRCTs was defective in DNA repair and sensitive to DNA damage, and full-length BRCA1 reversed these defects.

    “Confirming the essential role of the BRCTs for BRCA1’s DNA repair function, a breast cancer cell line that expressed a truncated BRCA1 lacking functional BRCTs was defective in DNA repair and sensitive to DNA damage; defects that were reversed upon complementation with a full-length BRCA1 protein [36].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] Scully R Ganesan S Vlasakova K Chen J Socolovsky M Livingston DM Genetic analysis of BRCA1 function in a defined tumor cell line Mol. Cell 1999 4 6 1093 1099 10635334 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BRCA1 patient mutations are distributed throughout the gene and target the N-terminal RING and C-terminal BRCT domains.

    “BRCA1 patient mutations were throughout the gene, targeting both the N-terminal RING and the C-terminal BRCT domains [34].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Scully R Livingston DM In search of the tumour-suppressor functions of BRCA1 and BRCA2 Nature 2000 408 6811 429 432 11100717 PMC2981135 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    At least four other distinct FANCJ-truncating mutations have been identified in breast cancer patients, but it is unclear whether these alleles express a truncated product.

    “Similarly, at least four other distinct FANCJ-truncating mutations have been identified in breast cancer patients [44]; however, it is not clear whether these alleles express a truncated product.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Seal S Thompson D Renwick A Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles Nat. Genet 2006 38 11 1239 1241 17033622 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    RAD51C mutations occur in breast cancer and in a consanguineous family with severe congenital abnormalities characteristic of Fanconi anemia.

    “Conceivably, RAD51C will also join the BRCA-FA family given that mutations were found not only in breast cancer [21], but also in a consanguineous family with severe congenital abnormalities characteristic of FA [31].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [21] Meindl A Hellebrand H Wiek C Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene Nat. Genet 2010 42 15 410 414 20400964 source

      Not checked in the free run.

    • cites [31] Vaz F Hanenberg H Schuster B Mutation of the RAD51C gene in a Fanconi anemia-like disorder Nat. Genet 2010 42 5 406 409 20400963 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Low-penetrance alleles deviate from traditional genetic patterns: highly penetrant alleles typically segregate with disease, whereas moderately penetrant alleles do not.

    “Highly penetrant alleles will typically segregate with disease, whereas moderately penetrant alleles will not.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [57] Stratton MR Rahman N The emerging landscape of breast cancer susceptibility Nat. Genet 2008 40 1 17 22 18163131 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    FANCJ is considered a low-to-moderate penetrance breast cancer susceptibility allele associated with modest two- to threefold increases in breast cancer risk.

    “All together, FANCJ is considered a low-to-moderate penetrance breast cancer susceptibility allele and is associated with modest two- to threefold increases in breast cancer risk [9,54].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] Nikkila J Coleman KA Morrissey D Familial breast cancer screening reveals an alteration in the RAP80 UIM domain that impairs DNA damage response function Oncogene 2009 16 28 1843 1852 19305427 PMC2692655 source

      Not checked in the free run.

    • cites [54] Walsh T King MC Ten genes for inherited breast cancer Cancer Cell 2007 11 2 103 105 17292821 ▪ Describes the link between breast cancer genes and FA. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    R798x is predicted to produce a truncated protein, but no detectable protein product was found.

    “The R798x mutation predicts a truncated protein, but a detectable protein product was not found [26].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] Litman R Peng M Jin Z BACH1 is critical for homologous recombination and appears to be the Fanconi anemia gene product FANCJ Cancer Cell 2005 8 3 255 265 16153896 ▪▪ The breast cancer gene BACH1/FANCJ was found to be bi-allelically mutated in the FA-J complementation group and essential for homologous recombination. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Bi-allelic mutations in BACH1/FANCJ/BRIP1 or PALB2/FANCN cause the FA subtypes FA-J or FA-N, respectively.

    “Similarly, inheriting bi-allelic mutations in BACH1/FANCJ/ BRIP1 or PALB2/FANCN genes results in the FA subtypes FA-J or FA-N, respectively (Figure 1) [26–30].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [26] Litman R Peng M Jin Z BACH1 is critical for homologous recombination and appears to be the Fanconi anemia gene product FANCJ Cancer Cell 2005 8 3 255 265 16153896 ▪▪ The breast cancer gene BACH1/FANCJ was found to be bi-allelically mutated in the FA-J complementation group and essential for homologous recombination. source

      Not checked in the free run.

    • cites [27] Levitus M Waisfisz Q Godthelp BC The DNA helicase BRIP1 is defective in Fanconi anemia complementation group J. Nat. Genet 2005 37 9 934 935 16116423 source

      Not checked in the free run.

    • cites [28] Levran O Attwooll C Henry RT The BRCA1-interacting helicase BRIP1 is deficient in Fanconi anemia Nat. Genet 2005 37 9 931 933 16116424 ▪▪ FANCJ was found to be bi-allelically mutated in the FA-J complementation group FA-J. source

      Not checked in the free run.

    • cites [29] Reid S Schindler D Hanenberg H Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer Nat. Genet 2007 39 2 162 164 17200671 source

      Not checked in the free run.

    • cites [30] Xia B Dorsman JC Ameziane N Fanconi anemia is associated with a defect in the BRCA2 partner PALB2 Nat. Genet 2007 39 2 159 161 17200672 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The C-terminus contains the phospho-SXXF motif at residues 990-993, which is required for BRCA1 binding.

    “Outside the helicase domain, the C-terminus harbors the phospho-SXXF motif (residues 990–993) required for BRCA1 binding (Figure 2) [37].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] Yu X Chini CC He M Mer G Chen J The BRCT domain is a phospho-protein binding domain Science 2003 302 5645 639 642 14576433 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The helicase domain contains a predicted nuclear localization sequence and an iron-sulfur cluster domain that are essential for enzyme activity and present in other DEAH helicases such as XPD, RTEL, and CHL1.

    “This region also harbors a predicted nuclear localization sequence, as well as the iron–sulfur (Fe–S) cluster domain, which are essential for enzyme activity and present in other DEAH helicases, such as XPD, RTEL and CHL1 [59].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [59] White MF Structure, function and evolution of the XPD family of iron–sulfur-containing 5′–>3′ DNA helicases Biochem. Soc. Trans 2009 37 Pt 3 547 551 19442249 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    FANCJ may participate with BRCA1 in resolving stalled replication forks or crosslinked DNA, which would explain the extreme sensitivity and massive chromosomal rearrangements seen in FANCJ- and BRCA1-deficient cells after interstrand crosslink agents.

    “Instead, FANCJ could participate with BRCA1 in a distinct aspect of DNA repair associated with resolving stalled replication forks or crosslinked DNA, a function that explains the extreme sensitivity and massive chromosomal rearrangements found in FANCJ- and BRCA1-deficient cells in response to agents that induce interstrand crosslinks [26].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] Litman R Peng M Jin Z BACH1 is critical for homologous recombination and appears to be the Fanconi anemia gene product FANCJ Cancer Cell 2005 8 3 255 265 16153896 ▪▪ The breast cancer gene BACH1/FANCJ was found to be bi-allelically mutated in the FA-J complementation group and essential for homologous recombination. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The breast cancer-associated P47A mutation and the FA-associated A349P mutation reduce FANCJ enzyme activity.

    “Consistent with enzyme activity being essential for tumor suppression, the breast cancer-associated mutation in helicase block II (P47A) or an FA-associated mutation in the Fe–S domain (A349P) reduced FANCJ enzyme activity [42,56,63].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [42] Wu Y Sommers JA Suhasini AN Fanconi anemia group J mutation abolishes its DNA repair function by uncoupling DNA translocation from helicase activity or disruption of protein–DNA complexes Blood 2010 116 19 3780 3791 20639400 PMC2981534 source

      Not checked in the free run.

    • cites [56] Cantor S Drapkin R Zhang F The BRCA1-associated protein BACH1 is a DNA helicase targeted by clinically relevant inactivating mutations Proc. Natl Acad. Sci. USA 2004 101 8 2357 2362 14983014 PMC356955 ▪ First study to demonstrate that mutations identified in breast cancer patients alter FANCJ function in vitro. source

      Not checked in the free run.

    • cites [63] Sommers JA Rawtani N Gupta R FANCJ uses its motor ATPase to disrupt protein–DNA complexes, unwind triplexes, and inhibit RAD51 strand exchange J. Biol. Chem 2009 284 12 7505 7517 19150983 PMC2658046 ▪ Demonstrates that FANCJ could alter recombination structures and proteins in DNA. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Wild-type FANCJ is a DNA-dependent ATPase that unwinds DNA in a 5′ to 3′ direction.

    “These studies revealed that wild-type FANCJ is a DNA-dependent ATPase, which unwinds DNA in a 5′ to 3′ direction [56].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] Cantor S Drapkin R Zhang F The BRCA1-associated protein BACH1 is a DNA helicase targeted by clinically relevant inactivating mutations Proc. Natl Acad. Sci. USA 2004 101 8 2357 2362 14983014 PMC356955 ▪ First study to demonstrate that mutations identified in breast cancer patients alter FANCJ function in vitro. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Loss of FANCJ function reduces genomic integrity through reduced repair and defective processing of distinct genomic DNA structures.

    “Based on the function of FANCJ, it is plausible that loss of FANCJ function will reduce genomic integrity not only because of reduced repair, but also because of defects in processing distinct genomic DNA structures.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    FANCJ transcription is cell growth-related and controlled by tumor suppressors of the E2F-retinoblastoma pathway.

    “It remains to be determined whether cancer is associated with changes in FANCJ transcription, which is cell growth-related and controlled by tumor suppressors of the E2F–retinoblastoma pathway [67].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [67] Eelen G Vanden Bempt I Verlinden L Expression of the BRCA1-interacting protein BRIP1/BACH1/FANCJ is driven by E2F and correlates with human breast cancer malignancy Oncogene 2008 27 30 4233 4241 18345034 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Tumor suppression likely requires both the helicase domain and nuclear co-localization with BRCA1, because variants in the nuclear localization sequence (A173C) or BRCA1-binding domain were detected in patients with a strong family history of breast cancer.

    “Tumor suppression likely requires not only the helicase domain, but also nuclear co-localization with BRCA1, given that variants with a sequence change in the nuclear localization sequence (A173C) [60] or BRCA1-binding domain were detected in patients with a strong family history of breast cancer [43,53].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [60] Luo L Lei H Du Q No mutations in the BACH1 gene in BRCA1 and BRCA2 negative breast-cancer families linked to 17q22 Int. J. Cancer 2002 98 4 638 639 11920628 source

      Not checked in the free run.

    • cites [43] De Nicolo A Tancredi M Lombardi G A novel breast cancer-associated BRIP1 (FANCJ/BACH1) germ-line mutation impairs protein stability and function Clin. Cancer Res 2008 14 14 4672 4680 18628483 PMC2561321 source

      Not checked in the free run.

    • cites [53] Cao AY Huang J Hu Z Mutation analysis of BRIP1/BACH1 in BRCA1/BRCA2 negative Chinese women with early onset breast cancer or affected relatives Breast Cancer Res. Treat 2009 115 1 51 55 18483852 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Expression of K52R attenuated replication stress-induced RPA chromatin association and checkpoint activation.

    “Furthermore, expression of K52R attenuated replication stress-induced RPA chromatin association and checkpoint activation [70].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [70] Gong Z Kim JE Leung CC Glover JN Chen J BACH1/FANCJ acts with TopBP1 and participates early in DNA replication checkpoint control Mol. Cell 2010 37 3 438 446 20159562 PMC3695484 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The A349P mutant retained some DNA unwinding activity on a set of substrates but could not couple ATP hydrolysis to unwinding forked duplex structures or DNA translocation.

    “Interestingly, the A349P mutant protein retained some DNA unwinding activity on a set of DNA substrates, but was unable to couple ATP hydrolysis with the enzyme activity necessary to unwind forked duplex structures or translocate DNA [42].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Wu Y Sommers JA Suhasini AN Fanconi anemia group J mutation abolishes its DNA repair function by uncoupling DNA translocation from helicase activity or disruption of protein–DNA complexes Blood 2010 116 19 3780 3791 20639400 PMC2981534 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FANCJ helicase activity induced in S phase is required for FANCJ to promote S phase progression and possibly intra-S phase checkpoints.

    “FANCJ helicase activity induced in S phase is also required for FANCJ to promote S phase progression and possibly intra-S phase checkpoints [71,72].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [71] Kumaraswamy E Shiekhattar R Activation of BRCA1/BRCA2-associated helicase BACH1 is required for timely progression through S phase Mol. Cell. Biol 2007 27 19 6733 6741 17664283 PMC2099226 ▪ Shows that FANCJ has a function that is independent of DNA repair in S phase progression. source

      Not checked in the free run.

    • cites [72] Greenberg RA Sobhian B Pathania S Cantor SB Nakatani Y Livingston DM Multifactorial contributions to an acute DNA damage response by BRCA1/BARD1-containing complexes Genes Dev 2006 20 1 34 46 16391231 PMC1356099 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Experiments using FANCJ-null FA-J patient cells complemented with K52R or A349P demonstrated that FANCJ enzyme activity and the Fe-S domain are essential for DNA interstrand crosslink repair.

    “Experiments using FANCJ-null FA-J patient cells complemented with K52R or the A349P FA-associated mutant demonstrated that FANCJ enzyme activity and the Fe–S domain are essential for DNA interstrand crosslink repair [42,73].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [42] Wu Y Sommers JA Suhasini AN Fanconi anemia group J mutation abolishes its DNA repair function by uncoupling DNA translocation from helicase activity or disruption of protein–DNA complexes Blood 2010 116 19 3780 3791 20639400 PMC2981534 source

      Not checked in the free run.

    • cites [73] Peng M Litman R Xie J Sharma S Brosh RM Jr Cantor SB The FANCJ/MutLα interaction is required for correction of the cross-link response in FA-J cells Embo J 2007 26 13 3238 3249 17581638 PMC1914102 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    Mutations outside the reading frame or promoter methylation changes could alter FANCJ expression and contribute to tumorigenesis.

    “Given that changes in BRCA1 promoter status contribute to sporadic tumors [64,65], mutations outside the reading frame or changes in promoter methylation status could alter FANCJ expression and contribute to tumorigenesis.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [64] Catteau A Harris WH Xu CF Solomon E Methylation of the BRCA1 promoter region in sporadic breast and ovarian cancer: correlation with disease characteristics Oncogene 1999 18 11 1957 1965 10208417 source

      Not checked in the free run.

    • cites [65] Esteller M Silva JM Dominguez G Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors J. Natl. Cancer Inst 2000 92 7 564 569 10749912 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    FANCJ enzyme activity is important for tumor-suppressor function, and helicase-domain mutations likely affect which DNA substrates FANCJ can metabolize.

    “These studies implicate that FANCJ enzyme activity is important for tumor-suppressor function and that mutations targeting the helicase domain likely dictate or have a detrimental effect on the type of DNA substrates FANCJ can metabolize.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Changes in BRCA1 promoter status contribute to sporadic tumors.

    “Given that changes in BRCA1 promoter status contribute to sporadic tumors [64,65], mutations outside the reading frame or changes in promoter methylation status could alter FANCJ expression and contribute to tumorigenesis.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [64] Catteau A Harris WH Xu CF Solomon E Methylation of the BRCA1 promoter region in sporadic breast and ovarian cancer: correlation with disease characteristics Oncogene 1999 18 11 1957 1965 10208417 source

      Not checked in the free run.

    • cites [65] Esteller M Silva JM Dominguez G Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors J. Natl. Cancer Inst 2000 92 7 564 569 10749912 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FA-J patient cells accumulate deletions in regions containing G4-DNA, and recombinant FANCJ A349P fails to unwind G4-DNA substrates.

    “In support of this function, FA-J patient cells accumulate deletions in regions containing G4-DNA, and the recombinant FANCJ A349P mutant protein fails to unwind G4-DNA substrates [42,79].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [42] Wu Y Sommers JA Suhasini AN Fanconi anemia group J mutation abolishes its DNA repair function by uncoupling DNA translocation from helicase activity or disruption of protein–DNA complexes Blood 2010 116 19 3780 3791 20639400 PMC2981534 source

      Not checked in the free run.

    • cites [79] London TB Barber LJ Mosedale G FANCJ is a structure-specific DNA helicase associated with the maintenance of genomic G/C tracts J. Biol. Chem 2008 283 52 36132 36139 18978354 PMC2662291 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    FANCJ enzyme activity is essential for DNA repair and checkpoint activation.

    “However, cell culture experiments revealed that FANCJ enzyme activity is essential for DNA repair as well as checkpoint activation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Reduced FANCJ expression and protein truncation characterize several FANCJ breast cancer mutations.

    “Thus, reduced FANCJ expression, as well as protein truncation, characterizes several FANCJ breast cancer mutations.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    FANCJ-associated tumors could be selectively sensitive to G4-DNA ligands such as telomestatin, which stabilize G4-DNA structures.

    “FANCJ-associated tumors could also be selectively sensitive to treatment with G4-DNA ligands such as telomestatin, which stabilize G4-DNA structures.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: FANCJ resolves DNA crosslinks and G4-DNA structures.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Whether a FANCJ mutation is enzyme inactivating or hyperactivating could determine the disease state.

    “A distinction of disease states could relate to whether a mutation in FANCJ is enzyme inactivating or hyperactivating (Figure 3).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    Clinically relevant FANCJ loss-of-function mutants are predicted to cause genomic instability through reduced DNA repair and checkpoint activation.

    “The predicted physiological consequence of clinically relevant FANCJ loss-of-function mutants is genomic instability due to reduced DNA repair and checkpoint activation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Targeting the translesion synthesis polymerase REV3 restores cisplatin sensitivity to lung tumors.

    “targeting the translesion synthesis polymerase REV3, which restores cisplatin sensitivity to lung tumors [82]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] Doles J Oliver TG Cameron ER Suppression of Rev3, the catalytic subunit of Polζ, sensitizes drug-resistant lung tumors to chemotherapy Proc. Natl Acad. Sci. USA 2010 107 48 20786 20791 21068376 PMC2996428 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    FANCJ is a helicase whose mutations are linked to human disease.

    “In summary, FANCJ is a disease-linked helicase.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The FANCJ S990A mutant reduces error-free homologous recombination repair and enhances error-prone DNA damage bypass through the Pol-η translesion synthesis polymerase.

    “In particular, the FANCJ S990A mutant reduced error-free repair by homologous recombination and enhanced error-prone DNA damage bypass through the Pol-η translesion synthesis polymerase [69].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [69] Xie J Litman R Wang S Targeting the FANCJ–BRCA1 interaction promotes a switch from recombination to poleta-dependent bypass Oncogene 2010 29 17 2499 2508 20173781 PMC2909592 ▪ Demonstrates that BRCA1 binding to FANCJ in human cells is essential for regulating the choice for DNA repair processing. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Mutations in BRCA1 and BRCA2 make the resulting tumors selectively sensitive to agents that create lesions requiring homologous recombination repair.

    “Mutations in BRCA1 and BRCA2 genes render derived tumors selectively sensitive to agents that generate lesions requiring DNA repair by homologous recombination.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    FANCJ helicase activity is needed for normal cellular repair and checkpoint signaling.

    “FANCJ helicase activity is important for normal cellular repair and checkpoint signaling”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    BRCA1 or FANCJ patient mutations that reduce their interaction may compromise genomic stability through reduced checkpoint control and DNA repair and through enhanced DNA damage tolerance.

    “Thus, BRCA1 or FANCJ patient mutations that reduce the interaction may compromise genomic stability not only because of reduced checkpoint control and DNA repair, but also owing to enhanced DNA damage tolerance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Studies of the BRCA1 interaction-defective FANCJ mutant S990A predict that loss of FANCJ binding to BRCA1 will enhance genomic instability through both reduced checkpoint and repair functions and enhanced DNA damage tolerance.

    “Studies on a BRCA1 interaction-defective mutant FANCJ S990A predict that loss of FANCJ binding to BRCA1 will enhance genomic instability not only owing to reduced checkpoint and repair functions, but also owing to enhanced DNA damage tolerance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Both reduced repair and enhanced bypass promote resistance to DNA crosslinking agents such as mitomycin C; bypass is more error-prone because lesions are tolerated rather than repaired.

    “Both mechanisms promote resistance to DNA crosslinking agents, such as mitomycin C; however, bypass is more error-prone because lesions are tolerated and not repaired.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    FANCJ enzyme defects could promote tumorigenesis through loss of G4-DNA structures and/or altered expression of genes harboring G4-DNA.

    “Thus, FANCJ enzyme defects could propel tumorigenesis due to loss of either G4-DNA structures and/or the expression of distinct genes harboring G4-DNA.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Elevated FANCJ expression levels were detected in grade 3 invasive breast tumors and correlated with poor prognosis.

    “In support of this possibility, elevated FANCJ expression levels were detected in grade 3 invasive breast tumors and correlated with poor prognosis [67].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [67] Eelen G Vanden Bempt I Verlinden L Expression of the BRCA1-interacting protein BRIP1/BACH1/FANCJ is driven by E2F and correlates with human breast cancer malignancy Oncogene 2008 27 30 4233 4241 18345034 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Mutations in the XPD helicase can cause at least three disease states: xeroderma pigmentosa, Cockayne syndrome, and trichothiodystrophy.

    “Mutations in the xeroderma pigmentosa helicase XPD can lead to at least three disease states including xeroderma pigmentosa, Cockayne syndrome and trichothiodystrophy [81].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [81] Fan L Fuss JO Cheng QJ XPD helicase structures and activities: insights into the cancer and aging phenotypes from XPD mutations Cell 2008 133 5 789 800 18510924 PMC3055247 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Bi-allelic inheritance of FANCJ mutations, like PALB2 and BRCA2 mutations, contributes to Fanconi anemia, a rare cancer-prone disease with extreme cellular sensitivity to interstrand crosslink-inducing agents.

    “Bi-allelic inheritance of mutations in FANCJ, similar to PALB2 and BRCA2, contributes to Fanconi anemia, a rare cancer-prone disease characterized by extreme cellular sensitivity to agents that induce DNA interstrand crosslinks.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    FANCJ functions in DNA repair and checkpoint control.

    “functions in DNA repair and checkpoint control.”
    Quote in the paperNot a substantial claim
55 of 55

  • The authors state this as an assumption.

    In families carrying secondary hits, the P47A allele segregates with cancer.

    “In this model, the P47A allele would segregate with cancer in families with secondary hits.”

  • The paper relies on this without support.

    The location of a FANCJ mutation can provide information about its functional consequences.

    “Even though the location of FANCJ mutations can provide information about functional consequences”

  • The paper relies on this without support.

    FANCJ resolves DNA crosslinks and G4-DNA structures.

    “The role of FANCJ in resolving not only DNA crosslinks, but also G4-DNA”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The 4 patients with deficiencies in BRCA1-binding proteins BARD1, BRIP1, FAM175A and FANCA were all predicted as having BRCA1-type HRD.

    “Likewise, the 4 patients with deficiencies in the BRCA1-binding proteins, BARD124 (n = 1), BRIP125 (n = 1), FAM175A26 (n = 1) and FANCA27 (n = 1), were all predicted as having BRCA1-type HRD.”

    From Pan-cancer landscape of homologous recombination deficiency. (2020) · cites this paper as [25]

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Related

Authors
Cantor, S. B., & Guillemette, S.
Affiliations
University of Massachusetts Chan Medical School (US)
Corresponding author
Cantor, Sharon B
ORCID
Cantor, Sharon B
Venue
Future Oncology
Publisher
Informa UK Limited
Published
2011-02-23
Volume
7
Issue
2
Pages
253-261
ISSN
  • 1479-6694 (ISSN-L)
  • 1744-8301
DOI
10.2217/fon.10.191
PMC
PMC3109611
OpenAlex
W2124616973
Cited by
106
References
83
Citations by year
2026: 5 · 2025: 6 · 2024: 3 · 2023: 8 · 2022: 6 · 2021: 10 · 2020: 5 · 2019: 6 · 2018: 7 · 2017: 7 · 2016: 8 · 2015: 4 · 2014: 6 · 2013: 14 · 2012: 9
FWCI
0.90
Type
journal article
Language
en
Open access
Locations
  • Future Oncology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
Shawna Guillemette (RO1 CA129514-01, T32CA130807)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
  • Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
Keywords
FANCJ, BACH1, BRIP1, hereditary breast cancer, BRCA1, Fanconi anemia, tumor suppressor, DNA helicase, DNA damage response, DNA repair, checkpoint control, DNA damage tolerance, targeted therapy
MeSH terms
Breast Neoplasms, DNA Repair, Fanconi Anemia, Female, Humans, Mutation, Gene Expression Regulation, Neoplastic, BRCA1 Protein, Tumor Suppressor Proteins, Basic-Leucine Zipper Transcription Factors, Fanconi Anemia Complementation Group Proteins

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-01.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-01.

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