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Updated: Oct 16, 2025
Single-Molecule Fluorescence Visualization of DNA Polymerase Dynamics at G-Quadruplexes
Published on: April 4, 2025
Unravelling roles of error-prone DNA polymerases in shaping cancer genomes
Cyrus Vaziri1, Igor B Rogozin2, Qisheng Gu3
1Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, 614 Brinkhous-Bullitt Building, Chapel Hill, NC, 27599, USA.
Abstract:
Mutagenesis is a key hallmark and enabling characteristic of cancer cells, yet the diverse underlying mutagenic mechanisms that shape cancer genomes are not understood. This review will consider the emerging challenge of determining how DNA damage response pathways-both tolerance and repair-act upon specific forms of DNA damage to generate mutations characteristic of tumors. DNA polymerases are typically the ultimate mutagenic effectors of DNA repair pathways. Therefore, understanding the contributions of DNA polymerases is critical to develop a more comprehensive picture of mutagenic mechanisms in tumors. Selection of an appropriate DNA polymerase-whether error-free or error-prone-for a particular DNA template is critical to the maintenance of genome stability. We review different modes of DNA polymerase dysregulation including mutation, polymorphism, and over-expression of the polymerases themselves or their associated activators. Based upon recent findings connecting DNA polymerases with specific mechanisms of mutagenesis, we propose that compensation for DNA repair defects by error-prone polymerases may be a general paradigm molding the mutational landscape of cancer cells. Notably, we demonstrate that correlation of error-prone polymerase expression with mutation burden in a subset of patient tumors from The Cancer Genome Atlas can identify mechanistic hypotheses for further testing. We contrast experimental approaches from broad, genome-wide strategies to approaches with a narrower focus on a few hundred base pairs of DNA. In addition, we consider recent developments in computational annotation of patient tumor data to identify patterns of mutagenesis. Finally, we discuss the innovations and future experiments that will develop a more comprehensive portrait of mutagenic mechanisms in human tumors.
Insights
Cancer cells use diverse mutagenic mechanisms, often involving DNA polymerases that repair or tolerate DNA damage. Error-prone polymerases may compensate for repair defects, shaping cancer genomes.
Area of Science:
- Genetics
- Molecular Biology
- Cancer Research
Background:
- Mutagenesis is a fundamental characteristic of cancer, but the specific mechanisms driving cancer genome mutations remain unclear.
- DNA damage response pathways, including repair and tolerance, play a crucial role in generating tumor-specific mutations.
- DNA polymerases are key effectors in these pathways, influencing genome stability through their error-free or error-prone activities.
Purpose of the Study:
- To review how DNA damage response pathways and DNA polymerases contribute to mutagenesis in cancer.
- To explore mechanisms of DNA polymerase dysregulation and their impact on cancer genomes.
- To propose and investigate the role of error-prone polymerases in compensating for DNA repair defects.
Main Methods:
- Review of existing literature on DNA repair, tolerance, and mutagenesis.
- Analysis of DNA polymerase dysregulation (mutation, polymorphism, overexpression).
- Correlation of error-prone polymerase expression with mutation burden in The Cancer Genome Atlas (TCGA) patient tumor data.
- Comparison of genome-wide and targeted experimental approaches.
- Consideration of computational annotation of tumor data.
Main Results:
- DNA polymerases are critical effectors in mutagenic mechanisms within tumors.
- Dysregulation of DNA polymerases (mutation, polymorphism, overexpression) contributes to genomic instability.
- Error-prone polymerases may act as a general mechanism to compensate for DNA repair defects in cancer cells.
- Correlation analysis in TCGA data supports hypotheses linking polymerase expression to mutation burden.
Conclusions:
- Understanding DNA polymerase function is essential for a comprehensive view of cancer mutagenesis.
- Error-prone polymerase activity compensating for DNA repair deficiencies is a potential paradigm in cancer genome evolution.
- Integrating diverse experimental and computational approaches is key to deciphering complex mutagenic landscapes in human tumors.
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