Sharon B Cantor PhD
|Institution||University of Massachusetts Medical School|
|Department||Molecular, Cell and Cancer Biology|
|Address||University of Massachusetts Medical School|
364 Plantation Street, LRB
Worcester MA 01605
Hereditary Breast Cancer
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 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 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.
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.
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