项目来源

美国卫生和人类服务部基金(HHS)

项目主持人

FINGERMAN, IAN M

项目受资助机构

UNIVERSITY OF VIRGINIA

项目编号

5R01CA060499-24

立项年度

2018

立项时间

未公开

研究期限

未知 / 未知

项目级别

国家级

受资助金额

355500.00美元

学科

Cancer; Genetics; Human Genome; Women's Health;

学科代码

未公开

基金类别

Non-SBIR/STTR RPGs

关键词

未公开

参与者

DUTTA, ANINDYA

参与机构

NATIONAL CANCER INSTITUTE

项目标书摘要：DESCRIPTION (provided by applicant): 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 inhibt 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.