Homologous recombination (HR) mediated repair of DNA double-strand breaks (DSB) utilizes a number of tumor suppressors like BRCA1, BRCA2, FA proteins, Nbs1, ATM, that are often mutated or repressed in cancers and cancer-predisposition syndromes. This project is based on our recent discovery that two ATPases/helicases closely related to the replicative DNA helicase MCM2-7, named MCM8 and MCM9, are intimately involved in initiating HR at DSBs. Furthermore cancer genomics projects have demonstrated that 10-12% of human cancers of certain types show homozygous deletions, point mutations or under-expression of these two genes. Thus MCM8 or MCM9 could be new tumor suppressors relevant for human cancer. In addition, cancers with mutations in BRCA1 or BRCA2 are more susceptible to drugs that cause interstrand crosslinks, like cisplatin, or inhibit poly-ADP ribose polymerase (PARP-1), like olaparib. Thus mutations in MCM8 or MCM9 may be a new biomarker for personalizing cancer therapy by predicting susceptibility to cisplatin or olaparib. Furthermore, since ATPase/helicases are eminently druggable, if the ATPase/helicase activity of MCM8-9 is important for HR, and if inhibition of MCM8-9 sensitizes a cancer to cisplatin or olaparib, the results will initiate a quest for small chemicals that inhibit MCM8-9 and thus sensitize tumors to cisplatin or olaparib. In the first Aim we will study the biochemistry and genetics of MCM8-9, characterizing its function in HR repair, and determining whether oligomerization, ATP binding or ATP hydrolysis are essential for its function. We will study exactly how MCM8-9 facilitates the formation of RPA-coated single-stranded DNA that is nearly the first step of HR. In the second Aim we will characterize whether the point mutations and deletions in MCM8 or MCM9 in human cancers inactivate the protein complex, compromise HR mediated DSB repair and sensitize the cells to cisplatin or olaparib. We will test whether loss of MCM9 promotes tumor progression in a genetic background that has inactivated other tumor suppressors such as PTEN, TGFBR2 or p53. Finally, we will test in mice whether loss of MCM9 sensitizes both xenografted human tumors and naturally occurring mouse tumors to cisplatin or olaparib.
Homologous recombination (HR) mediated repair of double-strand breaks in DNA is important for preventing cancers and failure of HR sensitizes cancers to specific chemotherapy drugs such as cisplatin or olaparib. The results from this project will elucidate the exact mechanism of how MCM8-9 proteins promote HR repair and demonstrate whether the loss of MCM8-9 seen in human cancers facilitates tumor progression, while at the same time compromising HR and making the cancers susceptible to cisplatin or olaparib. The project can elevate MCM8-9 status to an actionable biomarker for predicting the sensitivity of a cancer to cisplatin or olaparib. It will also identify a new tumor suppressor and paradoxically, a new target for novel drugs that can improve the efficacy of cisplatin or olaparib on cancers that do not have a mutation in HR pathways.
Showing the most recent 10 out of 89 publications
