Newswise – Irvine, California, March 18, 2024 – A research team led by the University of California, Irvine has discovered the key role that the enzymes APOBEC3A and APOBEC3B play in triggering cancer mutations by altering DNA in tumor genomes and providing potential new targets for intervention strategies.

The study was published online today in the journal Nature communicationdescribes how the researchers identified the process by which APOBEC3A and APOBEC3B recognize specific DNA structures, leading to mutations at specific positions in the tumor genome.

“It is important to understand how cancer cells accumulate mutations that lead to hot spots that contribute to disease progression, drug resistance and metastasis,” said corresponding author Rémi Buisson, UCI assistant professor of biological chemistry. “Both APOBEC3A and APOBEC3B were known to cause mutations in many types of tumors, but until now we did not know how to identify the specific type each causes. This insight will allow us to develop novel therapies to suppress mutation formation by directly targeting each enzyme accordingly.”

In this study, graduate student Ambrocio Sanchez and postdoctoral researcher Pedro Ortega, both in Buisson’s laboratory at the UCI School of Medicine, developed a new method to characterize the special type of DNA modified by APOBEC3A and APOBEC3B. It turned out that the two enzymes do not recognize the same DNA sequences and structures in the genome of cancer cells. Based on this observation, an innovative approach was used that exploited these unique target preferences to classify cancer patients who had accumulated mutations caused by each enzyme.

“The next steps will be to investigate whether mutations caused by these enzymes lead to different types of therapy resistance.” It is also important to identify molecules that inhibit APOBEC3A and APOBEC3B to prevent the formation of mutations. “In the future, our findings could help assess patient risk before treatment and suppress tumor development through appropriate drug therapy,” said Buisson.

Other team members included undergraduate and graduate students and postdoctoral fellows from UCI, Harvard Medical School, the University of Southern California, the University of Texas at San Antonio and the University of Minnesota.

This work was supported by the Research Supplements to Promote Diversity in Health-Related Research program of the National Institutes of Health under award R37-CA252081-S; California Institute for Regenerative Medicine Stem Cell Biology Training Grant TG2-01152; European Molecular Biology Organization Postdoctoral Fellowship ALTF 213-2023; Cancer Prevention and Research Institute of Texas Research Training Award RP 170345 and Established Investigator Recruitment CPRIT Award RR220053; the National Cancer Institute under awards R37-VA252081 and P01-CA234228; the National Institute of Allergy and Infectious Diseases under award R01 AI150524; and access to UCI’s Genomics Research and Technology Hub, affiliated with the Chao Family Comprehensive Cancer Center, under grant P30-CA062203.

About the University of California, Irvine: Founded in 1965, UCI is a member of the prestigious Association of American Universities and is ranked among the top ten public universities in the country US News and World Report. The campus has produced five Nobel Prize winners and is known for its academic achievements, world-class research, innovation and its anteater mascot. Under the leadership of Chancellor Howard Gillman, UCI has more than 36,000 students and offers 224 degree programs. Located in one of the safest and most economically vibrant communities in the world, the company is Orange County’s second-largest employer, contributing $7 billion annually to the local economy and $8 billion statewide. For more information about UCI, see www.uci.edu.

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