Yeast study suggests faulty proofreading is not to blame for link between cancer and DNA polymerase ε variants.
Accurate DNA replication is a matter of life and death. The polymerases responsible for replicating DNA have built-in safeguards to defend genome integrity, including proofreading activities to correct their own errors. Abnormally error-prone variants of DNA polymerase ε are linked to several types of cancer, and a popular hypothesis is that this is due to diminished proofreading ability. But new evidence published in G3 suggests otherwise.
In a yeast study of several mutant forms of DNA polymerase ε (Polε) associated with cancers, Barbari et al. show that the increased mutation rates of these wayward polymerases may not result from weakened proofreading alone. In fact, the vast majority of Polε exonuclease domain variants the group studied increased the yeast’s mutation rate more than a Polε variant that completely lacked proofreading ability did. Previous in vitro studies also showed that although the exonuclease activity Polε uses to excise mistakes is reduced in most of these variants, it is not eliminated. This means there must be other problems with these cancer-linked variants, the nature of which remain a mystery for now—though one clue is that they have amino acid substitutions in the DNA-binding cleft of Polε’s exonuclease domain.
The researchers also observed a correlation between the amount a Polε variant increased the yeast mutation rate and how common the variant was in tumors from a set of studies involving over 13,000 cases. In contrast, previous research found vastly different incidences in tumors among variants with similar impacts on exonuclease activity, providing further evidence that proofreading defects aren’t behind all cancers linked to faulty Polε. Barbari et al. don’t make any bold claims about what does cause these cancers, but given that 6% of colorectal tumors and 7% of endometrial tumors have Polε mutations, it’s clear further efforts must be dedicated to finding out.
CITATION:
Functional Analysis of Cancer-Associated DNA Polymerase ε Variants in Saccharomyces cerevisiae
Stephanie R. Barbari, Daniel P. Kane, Elizabeth A. Moore, Polina V. Shcherbakova
G3: Genes|Genomes|Genetics 2018 8: 1019-1029; https://doi.org/10.1534/g3.118.200042
http://www.g3journal.org/content/8/3/1019
Nicole Haloupek is a freelance science writer and a recent graduate of UC Berkeley's molecular and cell biology PhD program.
View all posts by Nicole Haloupek »Read more in
-
Early Career Leadership Spotlight: Julio Molina Pineda
We’re taking time to get to know the members of the GSA’s Early Career Scientist Committees. Join us to learn more about our early career scientist advocates. Julio Molina Pineda Policy and Advocacy University of Arkansas Research Interest My research interests focus on using model organisms to genetically dissect complex traits related to human disease. My…
-
Early Career Leadership Spotlight: Peiwei Chen
We’re taking time to get to know the members of the GSA’s Early Career Scientist Committees. Join us to learn more about our early career scientist advocates. Peiwei Chen Accessibility Subcommittee California Institute of Technology Research Interest Far from a harmonious place, the genome is a battleground, where every bit of DNA fights for inheritance and…
-
#Dros23 GSA Poster Award winners
We are pleased to announce the GSA Poster Award winners from the 64th Annual Drosophila Research Conference! Undergraduate and graduate student members of the GSA were eligible for the awards, and a hard-working team of postdocs volunteered their time as judges. Congratulations to all! Undergraduate Students 1st Place: Sofia Karter Lopez, University of Toronto “Rab11 mediates E-cadherin recycling during…
-
Congratulations to the Fall 2022 DeLill Nasser Awardees!
GSA is pleased to announce the recipients of the DeLill Nasser Award for Professional Development in Genetics for Fall 2022! Given twice a year to graduate students and postdoctoral researchers, DeLill Nasser Awards support attendance at meetings and laboratory courses. The award is named in honor of DeLill Nasser, a long-time GSA supporter and National Science Foundation…
-
New editors join GENETICS, G3 editorial boards
Several new editors are joining the GSA Journals. We’re excited to welcome Ricardo Zayas to the GENETICS editorial board under the Molecular Genetics of Development section, and on the G3: Genes|Genomes|Genetics board, we welcome Polly Campbell, Kevin Vogel, Joe Parker, and Ricardo Mallarino. Ricardo Zayas Associate Editor Ricardo Zayas is a Professor of Biology at…
-
Worms and Flies Provide Key Clues to Medical Mystery
This article is part of a series of posts outlining the history and impact of research in experimental organisms. The series is developed in collaboration with the GSA Public Communications and Engagement Committee. By the time Bertrand Might was six months old, it was clear something was amiss. His muscles weren’t developing normally; he was…
-
Congratulations to the 2023 Early Career Leadership Program Cohort!
The Genetics Society of America (GSA) is excited to announce the latest cohort of student, postdoc, and early-career research leaders joining the Early Career Leadership Program. Participants receive training and mentoring while serving on committees charged with understanding the needs, interests, concerns, and challenges of early career scientist members of the GSA. As part of…
-
GSA LOCI: Local Outreach Community Initiatives @ GSA Conferences
Highlights: Local Outreach Community Initiatives (LOCI): The Genetics Society of America is committed to supporting the communities of the host cities of our conferences. This new year, we are excited to reconnect with our GSA community in meaningful ways within and beyond our existing programming. The GSA membership has created a caring and supportive environment…
-
New members of the GSA Board of Directors: 2023–2025
We are pleased to announce the election of five new leaders to the GSA Board of Directors: 2023 Vice President/2024 President Mariana Wolfner Distinguished Professor of Molecular Biology and Genetics and Stephen H. Weiss Presidential Fellow My research has focused on the genes and pathways that mediate sexual development and reproduction, primarily in Drosophila. From…
-
Lance David Miller: Lighting Your Own Fire by Finding the Right Resources
By Daniel J. Gironda In the Paths to Science Policy series, we talk to individuals who have a passion for science policy and are active in advocacy through their various roles and careers. The series aims to inform and guide early career scientists interested in science policy. This series is brought to you by the…
-
Graça Almeida-Porada: The Importance of Communication in a Technologically Advancing World
By Daniel J. Gironda In the Paths to Science Policy series, we talk to individuals who have a passion for science policy and are active in advocacy through their various roles and careers. The series aims to inform and guide early career scientists interested in science policy. This series is brought to you by the…