A crucial first step in DNA repair involves the recognition of genome damage, which in turn activates signaling pathways that recruit effectors and resolve the lesion. However, whether this ?sensor- transducer-mediator? paradigm is generally applicable to pathways dedicated to repairing each distinct type of DNA lesion remains unknown. Understanding the signaling events that mediate the recognition and repair of DNA alkylation damage is particularly important, since alkylation chemotherapy is one of the most widely used systemic modalities for cancer treatment. Our preliminary studies demonstrate that human cells have a heretofore unrecognized repair signaling pathway that is highly specific for recruiting alkylation repair factors to nuclear foci and link this pathway to an inherited human disease. Since multiple alkylation repair factors appear to be recruited to these foci, we have termed them nuclear SCARs (Specialized Centers for Alkylation Repair). In this proposal, we seek to understand whether recruitment of alkylation repair factors to these sites is critical for resolution of alkylation repair (Aim 1). We will characterize the upstream E3 ubiquitin ligase, RNF113A, which we have found to play a central role in this pathway and is mutated in the progeroid syndrome trichothiodystrphy (Aim 2). Finally, we will test whether targeting this pathway could promote chemosensitization in human tumor models (Aim 3). These studies will greatly increase our understanding of how cells detect and activate DNA repair pathways. Since alkylation repair is critical for reversing the toxic effects of many chemotherapy agents, our work will provide new insights into how cell respond to such therapy, and may reveal several novel molecular targets for chemosensitization.

Public Health Relevance

We have discovered a new pathway by which human cells sense damage to their genomes and activate mechanisms to repair their DNA. This proposal seeks to understand the molecular basis for this pathway, its importance in cancer, and whether it can be targeted to improve cancer chemotherapy

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA227001-01
Application #
9500520
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Okano, Paul
Project Start
2018-07-01
Project End
2023-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Washington University
Department
Pathology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130