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    Sharon B Cantor PhD

    TitleAssociate Professor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentCancer Biology
    AddressUniversity of Massachusetts Medical School
    364 Plantation Street, LRB
    Worcester MA 01605
    Phone508-856-4421
      Other Positions
      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentCancer Biology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentInterdisciplinary Graduate Program

        Overview 
        Narrative

        Hereditary Breast Cancer

        Photo: Sharon Cantor

        Research in our group is focused on understanding how cells normally function to maintain genomic integrity and suppress cancer. In particular, we focus on the hereditary breast and ovarian cancer genes, BRCA1, BRCA2 and FANCJ (also known as BACH1 or BRIP1). FANCJ was named the BRCA1 Associated C-terminal Helicase (BACH1) because of its direct interaction with the C-terminal BRCA1-BRCT repeats and its ability to unwind the strands of DNA in an energy-dependent reaction. Human genetic studies resulted in the identification of two early-onset breast cancer patients with germ-line sequence changes in the FANCJ coding region. When these sequence changes were studied in vitro, both mutations resulted in a defective FANCJ protein. Interestingly, the (P47A) mutant disrupted and the (M299I) mutant enhanced the enzyme activity implicating that too little or too much enzyme activity predisposes to disease.

        Similar to BRCA2, FANCJ is also mutated in the cancer prone syndrome, Fanconi anemia (FA). FA is a chromosomal instability syndrome characterized by and cellular hypersensitivity to DNA crosslinking agents, such as cisplatin. FA is a multi-genetic disease with at least 13 complementation groups identified and referred to as FA-A through FA-N. BRCA2 is the FANCD1 gene mutated in the FA-D1 complementation group whereas FANCJ is mutated in the FA-J complementation group. So far, FA associated mutations in FANCJ appear to be enzyme inactivating or disrupt FANCJ expression.

        Research indicates that proteins functioning in the so-called, FA-BRCA pathway suppress cancer because of roles in preserving the integrity of the genome. The FA-BRCA proteins function to repair DNA lesions, such as DNA inter-strand crosslinks through several activities including the promotion of homologous recombination (HR). HR is a relatively error-free mechanism to repair DNA double strand breaks. In addition, the FA-BRCA pathway has roles in promoting DNA damage tolerance through translesion synthesis, a typically error-prone mechanism. By functioning together in large complexes, the FA-BRCA proteins can reverse toxic DNA crosslinks with minimal error generation and restart replication forks.

        The laboratory is interested in a range of repair-related topics including (i) the role of FANCJ in DNA repair, DNA damage tolerance, and checkpoint signaling and how these functions contribute to tumor suppression (ii) how FANCJ function is regulated by direct interactions with BRCA1 and MLH1, a mismatch repair protein, (iii) the relationship between FANCJ, BRCA1, and MLH1 in DNA crosslink repair, (iv) identifying novel FANCJ protein modifications or interacting partners that contribute to the function of FANCJ in the DNA damage response and (v) understanding the underlying defects associated with loss of function of proteins in the BRCA-FA pathway and whether these defects can be suppressed.

        The long-term objective of our research is to use our basic understanding of the FA-BRCA pathway to identify clinical applications in the treatment of FA-BRCA associated cancers or syndromes.

        Rotation Projects



        Rotation projects are available to study the role of the BACH1/FANCJ DNA helicase in the DNA damage response and tumor suppression.  We have uncovered that FANCJ contributes to both error-free and error-prone DNA damage response pathways.   Error-prone pathways are essential for cells to survive certain forms of DNA damage.  However, when not properly regulated error-prone pathways contribute to genomic instability, cancer, and chemoresistance. Our data indicate that dysregulation of error-prone pathways is a consequence of FANCJ breast cancer mutations.  Moreover, we identified DNA damage induced post-translational modifications that regulate FANCJ function and its contribution to DNA damage pathway choice. Rotation projects include dissecting whether FANCJ clinical mutations interfere with FANCJ post-translational modifcations.  Do FANCJ clinical mutants exclusively promote error-prone lesion processing? In addition, we are interested in elucidating the mechanism by which FANCJ contributes to DNA repair pathway choice.  In particular, FANCJ could contribute to repair choice using its DNA helicase/ translocase activity. The goal will be to analyze whether FANCJ unwinds DNA substrates and/or displacing proteins, to enhance DNA lesion processing by a distinct set of repair factors. 



        Post Docs

        A post-doctoral position is available immediately to study the role of genes found in a genome-wide RNAi screen to regulate the cellular response to the chemotherapy agent, cisplatin. The goal is to determine whether these genes function as tumor suppressor and/or regulate the mechanism of DNA repair processing.  The laboratory is interested in understanding the role of hereditary cancer genes of the BRCA-Fanconi anemia pathway in DNA damage repair and tumor suppression.  We seek motivated candidates with a PhD and background in cancer cell biology.  Experience in mouse cancer models is desirable. The exceptional training environment within the Department of Cancer Biology at UMASS Medical School offers a rigorous and interactive research environment covering several aspects of tumor biology.  Applicants should have excellent communication skills, and ability to conduct research independently and as a team. To apply, please send your CV with bibliography, a brief description of research experience and contact information for at least two references via email. 



        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Peng M, Xie J, Ucher A, Stavnezer J, Cantor SB. Crosstalk between BRCA-Fanconi anemia and mismatch repair pathways prevents MSH2-dependent aberrant DNA damage responses. EMBO J. 2014 Aug 1; 33(15):1698-712.
          View in: PubMed
        2. Guillemette S, Branagan A, Peng M, Dhruva A, Schärer OD, Cantor SB. FANCJ Localization by Mismatch Repair Is Vital to Maintain Genomic Integrity after UV Irradiation. Cancer Res. 2014 Feb 1; 74(3):932-44.
          View in: PubMed
        3. Suhasini AN, Sommers JA, Muniandy PA, Coulombe Y, Cantor SB, Masson JY, Seidman MM, Brosh RM. Fanconi anemia group J helicase and MRE11 nuclease interact to facilitate the DNA damage response. Mol Cell Biol. 2013 Jun; 33(11):2212-27.
          View in: PubMed
        4. Xie J, Peng M, Guillemette S, Quan S, Maniatis S, Wu Y, Venkatesh A, Shaffer SA, Brosh RM, Cantor SB. FANCJ/BACH1 acetylation at lysine 1249 regulates the DNA damage response. PLoS Genet. 2012 Jul; 8(7):e1002786.
          View in: PubMed
        5. Cantor SB, Guillemette S. Hereditary breast cancer and the BRCA1-associated FANCJ/BACH1/BRIP1. Future Oncol. 2011 Feb; 7(2):253-61.
          View in: PubMed
        6. Suhasini AN, Rawtani NA, Wu Y, Sommers JA, Sharma S, Mosedale G, North PS, Cantor SB, Hickson ID, Brosh RM. Interaction between the helicases genetically linked to Fanconi anemia group J and Bloom's syndrome. EMBO J. 2011 Feb 16; 30(4):692-705.
          View in: PubMed
        7. Xie J, Guillemette S, Peng M, Gilbert C, Buermeyer A, Cantor SB. An MLH1 mutation links BACH1/FANCJ to colon cancer, signaling, and insight toward directed therapy. Cancer Prev Res (Phila). 2010 Nov; 3(11):1409-16.
          View in: PubMed
        8. Cantor SB, Xie J. Assessing the link between BACH1/FANCJ and MLH1 in DNA crosslink repair. Environ Mol Mutagen. 2010 Jul; 51(6):500-7.
          View in: PubMed
        9. Sommers JA, Rawtani N, Gupta R, Bugreev DV, Mazin AV, Cantor SB, Brosh RM. FANCJ uses its motor ATPase to destabilize protein-DNA complexes, unwind triplexes, and inhibit RAD51 strand exchange. J Biol Chem. 2009 Mar 20; 284(12):7505-17.
          View in: PubMed
        10. Siehler SY, Schrauder M, Gerischer U, Cantor S, Marra G, Wiesmüller L. Human MutL-complexes monitor homologous recombination independently of mismatch repair. DNA Repair (Amst). 2009 Feb 1; 8(2):242-52.
          View in: PubMed
        11. Barber LJ, Youds JL, Ward JD, McIlwraith MJ, O'Neil NJ, Petalcorin MI, Martin JS, Collis SJ, Cantor SB, Auclair M, Tissenbaum H, West SC, Rose AM, Boulton SJ. RTEL1 maintains genomic stability by suppressing homologous recombination. Cell. 2008 Oct 17; 135(2):261-71.
          View in: PubMed
        12. Litman R, Gupta R, Brosh RM, Cantor SB. BRCA-FA pathway as a target for anti-tumor drugs. Anticancer Agents Med Chem. 2008 May; 8(4):426-30.
          View in: PubMed
        13. Gupta R, Sharma S, Sommers JA, Kenny MK, Cantor SB, Brosh RM. FANCJ (BACH1) helicase forms DNA damage inducible foci with replication protein A and interacts physically and functionally with the single-stranded DNA-binding protein. Blood. 2007 Oct 1; 110(7):2390-8.
          View in: PubMed
        14. Peng M, Litman R, Xie J, Sharma S, Brosh RM, Cantor SB. The FANCJ/MutLalpha interaction is required for correction of the cross-link response in FA-J cells. EMBO J. 2007 Jul 11; 26(13):3238-49.
          View in: PubMed
        15. Gupta R, Sharma S, Doherty KM, Sommers JA, Cantor SB, Brosh RM. Inhibition of BACH1 (FANCJ) helicase by backbone discontinuity is overcome by increased motor ATPase or length of loading strand. Nucleic Acids Res. 2006; 34(22):6673-83.
          View in: PubMed
        16. Cantor SB, Andreassen PR. Assessing the link between BACH1 and BRCA1 in the FA pathway. Cell Cycle. 2006 Jan; 5(2):164-7.
          View in: PubMed
        17. 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 Jan 1; 20(1):34-46.
          View in: PubMed
        18. Litman R, Peng M, Jin Z, Zhang F, Zhang J, Powell S, Andreassen PR, Cantor SB. BACH1 is critical for homologous recombination and appears to be the Fanconi anemia gene product FANCJ. Cancer Cell. 2005 Sep; 8(3):255-65.
          View in: PubMed
        19. Gupta R, Sharma S, Sommers JA, Jin Z, Cantor SB, Brosh RM. Analysis of the DNA substrate specificity of the human BACH1 helicase associated with breast cancer. J Biol Chem. 2005 Jul 8; 280(27):25450-60.
          View in: PubMed
        20. Cantor S, Drapkin R, Zhang F, Lin Y, Han J, Pamidi S, Livingston DM. The BRCA1-associated protein BACH1 is a DNA helicase targeted by clinically relevant inactivating mutations. Proc Natl Acad Sci U S A. 2004 Feb 24; 101(8):2357-62.
          View in: PubMed
        21. Joo WS, Jeffrey PD, Cantor SB, Finnin MS, Livingston DM, Pavletich NP. Structure of the 53BP1 BRCT region bound to p53 and its comparison to the Brca1 BRCT structure. Genes Dev. 2002 Mar 1; 16(5):583-93.
          View in: PubMed
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