Spartan Protease Repairs DNA-Protein Cross-Links (DPCs) and Prevents DPC-Induced Oncogensis Patients with bi-allelic mutations in Spartan, termed Ruijs-Aalfs (RJALS) syndrome, are prone to early-onset hepatocellular carcinoma (HCC) and segmental progeria. Spartan was initially characterized for its role in promoting cell survival upon UV-damage. Recently, the metalloprotease activity of the SprT domain of Spartan has been shown to cleave DNA-protein crosslinks (DPCs). DPCs are toxic lesions that stall replication forks during DNA replication. Unrepaired forks lead to DNA breaks and fork collapse, leading to genome instability, cell death or senescence. DPC repair has been shown to be mediated by specific enzymes such as tyrosyl- DNA phosphodiesterase, nucleases and/or the coordinated action of nucleotide excision repair and homologous recombination DNA repair pathways in some cases. However, the precise mechanism underlying DPC repair is largely unclear. This proposed study is designed to evaluate the molecular mechanism by which Spartan mediates the removal of DPCs at stalled replication forks. We will investigate the effect of RJALS patient mutations on the tumor suppressor functions of Spartan in hepatocellular carcinoma in vitro and in vivo and target Spartan and Spartan-mediated DPC repair as cancer therapeutics. Investigating the functions of Spartan in DPC repair will not only advance our understanding of the mechanism of RJALF syndrome, but will also help evaluate the potential of sensitizing cancer cells to chemotherapy by targeting Spartan protease and Spartan mediated DPC repair pathway.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
5P20GM121316-03
Application #
9920175
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
2020-03-01
Budget End
2021-02-28
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Nebraska Medical Center
Department
Type
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198