O-linked N-acetyglucosaminylation (O-GlcNAcylation) is a reversible posttranslational modification that plays a key role in ionizing radiation (IR)-induced DNA damage response. O-GlcNAcylation is catalyzed by O- GlcNActransferase (OGT), which transfers N-acetyl-D-glucosamine from UDP-GlcNAc to serine or threonine residues of proteins. This posttranslational modification is also removed by O-GlcNAcase (OGA). In our studies, we have shown that O-GlcNAcylation is significantly enriched at DNA lesions. Since the acceptors of O-GlcNAcylation are serine or threonine residues, O-GlcNAcylation competes with DNA damage-induced phosphorylation, which in turn regulates DNA damage repair. Thus, we hypothesize that O-GlcNAcylation is a key molecular event in response to IR treatment, and targeting O-GlcNAcylation can be an effective therapeutic strategy to cancer treatment. In this research proposal, we plan to focus on one major O-GlcNAcylation substrate MDC1, and examine the role of O-GlcNAcylated MDC1 in DNA damage response including the phosphorylation events on MDC1, MDC1 governed protein ubiquitination cascade, and DNA double-strand break repair. Using O-GlcNAcylated MDC1 as the readouts, we will analyze the biological functions of both OGT and OGA in IR-induced DNA damage repair, and explore the inhibition of OGA as a novel therapeutic strategy to treat BRCA1 or BRCA2- deficient tumors in vivo.

Public Health Relevance

O-GlcNAcylation is a unique posttranslational modification and plays a key role in repair of ionizing radiation-induced DNA double-strand breaks. In our preliminary study, we have shown that O-GlcNAcylation is remarkably enriched at DNA lesions and competes with DNA damage-induced phosphorylation events. In this application, we plan to examine the detailed molecular mechanism of O-GlcNAcylation in DNA damage response with focusing on ?writer? and ?eraser? enzymes, which may generate impact for future cancer therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA240392-02
Application #
9933871
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Oberdoerffer, Philipp
Project Start
2019-06-01
Project End
2024-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Beckman Research Institute/City of Hope
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010