Uridine homeostatic disorder leads to DNA damage and tumorigenesis

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Uridine is a naturally occurring nucleoside essential for biological processes.
• Its role in disease, particularly cancer, is not fully understood.
• Pharmacological administration of uridine has potential clinical applications but requires safety evaluation.

Purpose of the Study:

• To investigate the carcinogenic potential of uridine homeostatic disorder.
• To explore the molecular mechanisms linking uridine imbalance to tumorigenesis.
• To assess the impact of elevated uridine levels on DNA integrity and cellular responses.

Main Methods:

• Targeted disruption of murine uridine phosphorylase (UPase) to induce uridine imbalance.
• Monitoring spontaneous tumor development in UPase-deficient and wild-type mice.
• Quantifying 2'-deoxyuridine,5'-triphosphate (dUTP) and uracil DNA levels in tissues.
• Assessing p53 activation and DNA damage response markers (phospho-Ser18 p53, phospho-ATM, phospho-CHK2, phospho-γH2AX) in vivo and in cell lines.
• Treating cancer cell lines (MCF-7, RKO, HCT-8, NCI-H460) with uridine to induce DNA damage.

Main Results:

• UPase deficiency significantly increased spontaneous tumorigenesis (>3-fold) in mice.
• UPase-null mice developed multiple tumors, including lymphoma, hepatoma, and lung adenoma.
• Elevated dUTP and uracil DNA levels were observed in UPase-deficient mouse tissues.
• Uridine treatment in cell lines induced uracil DNA damage and activated the DNA damage response pathway, including p53, ATM, CHK2, and γH2AX.
• Increased phospho-Ser18 p53 levels indicated p53 activation in UPase-deficient mice.

Conclusions:

• Disruption of uridine homeostasis is carcinogenic, leading to increased tumor incidence.
• Elevated uridine levels cause uracil DNA damage and activate the p53-mediated DNA damage response.
• Pharmacological uridine may pose a carcinogenic risk due to its potential to induce DNA damage.