We use cookies to understand how you use our site and to improve your experience. This includes personalizing content and advertising. To learn more, click here. By continuing to use our site, you accept our use of cookies. Cookie Policy.

Features Partner Sites Information LinkXpress hp
Sign In
Advertise with Us
LGC Clinical Diagnostics

Download Mobile App




Salvage of DNA Precursors Is Lethal to Some Cancer Cells

By LabMedica International staff writers
Posted on 04 Aug 2015
Print article
Image: Structure of the CDA protein (Photo courtesy of Wikimedia Commons).
Image: Structure of the CDA protein (Photo courtesy of Wikimedia Commons).
Cancer cells overexpress the enzyme cytidine deaminase (CDA), which allows them to recycle inappropriate DNA precursors but renders them susceptible to genetic damage and cell death.

Cells require nucleotides to support DNA replication and repair damaged DNA. In addition to making these DNA precursors from scratch, cells recycle nucleotides from the DNA of dying cells or from cellular material ingested through the diet. However, salvaged nucleotides come with the complication that they can contain epigenetic modifications such as being methylated or phosphorylated.

In humans, cytidine deaminase is an enzyme involved in pyrimidine salvaging that is encoded by the CDA gene. This protein forms a homotetramer that catalyzes the irreversible hydrolytic deamination of cytidine and deoxycytidine to uridine and deoxyuridine, respectively. It is one of several deaminases responsible for maintaining the cellular pyrimidine pool. Mutations in this gene are associated with decreased sensitivity to the cytosine nucleoside analogue cytosine arabinoside used in the treatment of certain childhood leukemias.

Investigators at the University of Oxford (United Kingdom) reported in the July 22, 2015, online edition of the journal Nature that in normal cells the enzymes of the nucleotide salvage pathway displayed substrate selectivity, effectively protecting newly synthesized DNA from the incorporation of epigenetically modified forms of cytosine. Thus, cell lines and animals could tolerate high doses of these modified cytidines without any deleterious effects on physiology.

In contrast, by screening cancer cell lines for growth defects after exposure to 5hmdC (5-hydroxymethyl-2′deoxycytidine), the investigators unexpectedly identified a subset of cell lines in which 5hmdC or 5fdC (5-formy-2′deoxycytidine) led to cell death. Using genomic approaches, they showed that the susceptible cell lines overexpressed CDA. CDA converted 5hmdC and 5fdC into variants of uridine that were incorporated into DNA, resulting in accumulation of DNA damage, and ultimately, cell death.

"In the past few years we and others discovered a new set of biological DNA modifications. In the current study, our research group sought to find out what happens to these modified bases when DNA is recycled," said senior author Dr. Skirmantas Kriaucionis, assistant member of the Ludwig Institute for Cancer Research at the University of Oxford. "We were excited that our biochemical analysis uncovered "loopholes," which we hope can be exploited for intervention in cancer. It has been suggested that CDA inactivates cytidine analogues that are already used in the clinic to treat some blood and pancreatic cancers. In a strikingly reverse scenario, the nucleotides that we used in our study are relatively harmless until they encounter CDA, which converts them into hostile cytotoxic agents."

Related Links:

University of Oxford


Gold Member
Turnkey Packaging Solution
HLX
Automated Blood Typing System
IH-500 NEXT
New
Lab Sample Rotator
H5600 Revolver
New
Nuclear Matrix Protein 22 Test
NMP22 Test

Print article

Channels

Clinical Chemistry

view channel
Image: The new saliva-based test for heart failure measures two biomarkers in about 15 minutes (Photo courtesy of Trey Pittman)

POC Saliva Testing Device Predicts Heart Failure in 15 Minutes

Heart failure is a serious condition where the heart muscle is unable to pump sufficient oxygen-rich blood throughout the body. It ranks as a major cause of death globally and is particularly fatal for... Read more

Hematology

view channel
Image: The smartphone technology measures blood hemoglobin levels from a digital photo of the inner eyelid (Photo courtesy of Purdue University)

First-Of-Its-Kind Smartphone Technology Noninvasively Measures Blood Hemoglobin Levels at POC

Blood hemoglobin tests are among the most frequently conducted blood tests, as hemoglobin levels can provide vital insights into various health conditions. However, traditional tests are often underutilized... Read more

Immunology

view channel
Image: Under a microscope, DNA repair is visible as bright green spots (“foci”) in the blue-stained cell DNA. Orange highlights actively growing cancer cells (Photo courtesy of WEHI)

Simple Blood Test Could Detect Drug Resistance in Ovarian Cancer Patients

Every year, hundreds of thousands of women across the world are diagnosed with ovarian and breast cancer. PARP inhibitors (PARPi) therapy has been a major advancement in treating these cancers, particularly... Read more

Microbiology

view channel
Image: HNL Dimer can be a novel and potentially useful clinical tool in antibiotic stewardship in sepsis (Photo courtesy of Shutterstock)

Unique Blood Biomarker Shown to Effectively Monitor Sepsis Treatment

Sepsis remains a growing problem across the world, linked to high rates of mortality and morbidity. Timely and accurate diagnosis, along with effective supportive therapy, is essential in reducing sepsis-related... Read more
Copyright © 2000-2024 Globetech Media. All rights reserved.