Sharon Cantor, PhD
The Cantor laboratory currently studies two genes that are associated with hereditary cancer:
BRCA1
BRCA2
Mutations in these genes predispose women to early onset breast and ovarian cancer. Dr Cantor's research efforts have focused on gaining mechanistic insights into the BRCA1-mediated DNA repair and tumor suppression.
While human genetics makes it clear that these genes function as tumor suppressors, it is still unclear how these proteins function. Dr. Cantor's research efforts have focused on gaining mechanistic insights into the BRCA1-mediated DNA repair and tumor suppression. We found that the ability of BRCA1 to effectively mediate repair of DNA damage depends on the ability of BRCA1 to directly associate with a novel protein we identified and called BACH1 (BRCA1 Associated C-terminal Helicase). BACH1 is an enzyme that can unwind the strands of DNA in an energy-dependent reaction. This activity is critical for its role in DNA repair.
Human genetic studies resulted in the identification of two early-onset breast cancer patients with germline sequence changes in the BACH1 coding region. When these sequence changes were studied in vitro, we found that both mutations resulted in defective BACH1 proteins unable to effectively function as DNA helicases.
This data provides a biochemical link to human disease-predisposing mutations in BACH1 and suggest that BACH1 helicase activity is critical for biological function. We are actively pursuing these studies on BACH1 in order to more clearly define its biological role in normal cell physiology and ultimately determine why mutations in BACH1 and BRCA1 lead to breast and ovarian cancers. One major question stemming from this work is whether of BACH1 is a breast cancer helicase?
Current Research Projects in the Cantor Laboratory
National Institutes of Health-National Cancer Institute
- R01CA129514: BACH1/FANCJ Checkpoint, Recombination, and Chemoresistance
We have identified that BACH1 binds directly to MLH1 and that a mutant version of BACH1 ablated for MLH1 binding failed to elicit an interstrand crosslink (ICL)-induced checkpoint response. We will test this possibility directly. In addition, we will determine whether BACH1 also participates in the DNA-methylation-induced G2/M accumulation checkpoint similar to MutL1. We propose to dissect the role of a BACH1/MutL1 complex in both checkpoint and repair functions. We will determine whether the formation of an intact complex is required to restore chemosensitivity to resistant null BACH1 or MutL1 cells.