First systematic report on the tug-of-war between DNA damage and repair

June 08, 2020

A collaborative project between the Center for Genome Integrity, within the Institute for Basic Science (IBS, South Korea), and the Dundee School of Life Sciences, the EMBL's European Bioinformatics Institute (EMBL-EBI), and the Wellcome Sanger Institute (UK) have screened almost 163,000 DNA mutations in 2,700 C. elegans roundworms to shed light on DNA damage. The results, published in Nature Communications, lead to the conclusion that mutation patterns seen in cancer are more complicated than we previously thought.

Our genetic material is constantly exposed to possible sources of mutations, including UV light, tobacco smoke and carcinogenic chemicals. These genetic alterations are usually corrected by an army of DNA repair proteins that patrol the DNA and fix its mistakes. However, what happens when the policemen themselves are malfunctioning? They can overlook some DNA alterations, or even generate some mutations while trying to correct them. In this study, researchers looked at mutational signatures - patterns of mutations occurring in the genome - caused by the combined action of 11 known DNA damaging agents and inaccurate DNA repair mechanisms using C. elegans worms as a model system.

"Our paper is the first to use experimental approaches to systematically test, at a genome-wide scale, how DNA damaging agents cause mutations, and how this is prevented by DNA repair proteins," says Anton Gartner, Associate Director of the IBS Center for Genomic Integrity and co-leading author of this study.

While mutagens were thought to generate unique mutational signatures, the results showed a more intricate picture. DNA repair pathways are highly redundant: up to four different repair pathways act together to prevent mutagenesis caused by the same cancer inducing agents. Using roundworms with 53 different DNA repair deficits, the researchers found out that a single mutagen may leave a variety of mutational signatures depending on the faulty repair system.

This study is particularly important because unmended mutations in specific parts of the DNA can lead to cancer. Since fundamental processes, such as DNA repair, are conserved throughout evolution, the team was able to use data derived from C. elegans to scan through thousands of human cancer genome sequences and find possible evidence for mutagenic events linked to faulty DNA repair systems.

Over the past years, mutational signatures of cancer have been deduced from computational analyses. Some of these signatures could be associated with suspected mutagenic causes, such as the exposure to UV light for melanomas, or exposure to aflatoxin for liver cancer. However, the cause of the majority of these mutational signatures observed in cancer is not known. In most cases, it is unclear if there is a direct one-to-one relationship between the mutational signatures and a single mutagen. This paper reports that mutational signatures are due to a combination of factors, 'offending' DNA damaging agents and cellular policemen that properly do their job most of the time, but in some cases allow culprits to escape.
-end-


Institute for Basic Science

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.