DNA with Translesion Synthesis activity.

Decoding DNA Damage: How Translesion Synthesis Can Both Prevent and Promote Cancer

Soraya Malik in Science & Nature September 2025 • 4 min read.

"Unraveling the complex role of translesion synthesis (TLS) in cancer, from preventing mutations to potentially fueling tumor growth, and what it means for future treatments."

In the relentless battle against cancer, scientists are constantly seeking to understand the intricate mechanisms that govern cellular transformation. A critical step in this process involves mutations in the DNA of cells, often triggered by exposure to genotoxic agents. When DNA is damaged, cells employ various repair strategies, one of which is translesion DNA synthesis (TLS). But here's the twist: TLS, while intended to fix things, can sometimes contribute to the very problem it's trying to solve.

Translesion DNA synthesis (TLS) is essentially a cellular workaround. It allows cells to replicate DNA even when it contains unrepaired damage that would normally halt the replication fork. Think of it as a detour around a roadblock. The enzymes responsible for TLS in mammals, known as TLS polymerases, have been a hot topic of research. Among these, DNA polymerase η (Pol η) is the most well-understood, known for its role in the error-free bypass of UV-induced DNA damage.

Other TLS polymerases, including Pol ι, Pol κ, REV1, and Pol ζ, have been extensively studied in vitro. However, their roles in living organisms are only now being investigated through knockout mouse models of carcinogenesis. By examining mice and humans with altered expression of TLS polymerases, researchers are gaining insights into the effects of these enzymes on cancer induced by environmental agents.

TLS Polymerases: Guardians or Gamblers in the Genetic Code?

DNA with Translesion Synthesis activity.

Tumorigenesis, the multistep process by which normal cells transform into cancerous ones, hinges on the accumulation of distinct characteristics: limitless replication, resistance to growth-suppressing signals and apoptosis, self-sufficient growth signals, sustained angiogenesis (blood vessel formation), and tissue invasion. Environmental carcinogens often trigger this transformation by inducing mutations in DNA, which then alter the function of proto-oncogenes (genes that promote cell growth) or tumor suppressors (genes that inhibit cell growth).

These mutations arise when residual, unrepaired DNA damage stalls the replication fork during cell division. While cells have mechanisms to resolve these stalled forks, sometimes replication proceeds using the damaged strand as a template. This error-prone process is TLS. Defined as the incorporation of a nucleotide across from DNA damage and subsequent extension, TLS can be either error-free or error-prone. The decision between error-free repair, recombination, or error-prone TLS is governed by the molecular switch PCNA (proliferating cell nuclear antigen).

Error-Free TLS: Involves using specialized polymerases like Pol η to accurately copy past damage.
Error-Prone TLS: Utilizes other polymerases that may introduce mutations during the bypass.
Recombination: Involves using a homologous template to bypass the damaged area.

Cells essentially gamble, risking mutations caused by TLS to relieve replication fork blockage at DNA adducts (DNA segments bound to a cancer-causing chemical) and to avoid the formation of extremely cytotoxic double-strand breaks (DSB). Although TLS accounts for less than 10% of all bypass synthesis events in yeast, the frequency of potentially mutagenic TLS may be as high as 50% in higher eukaryotes. This propensity and mutagenic potential explain why TLS is implicated in most environmentally induced cancers and has been the focus of investigations.

The Balancing Act: TLS as a Double-Edged Sword

The importance of translesion DNA synthesis in preventing human cancer is evident in XP variant patients, who, lacking the Y-family DNA polymerase η, are prone to UV-induced skin cancers due to extreme hypermutability. But recent mouse models present conflicting results. Ribozyme-mediated knockdown of total Rev1 and removal of the BRCT domain both result in reduced mutagenesis by BPDE or UV, respectively. However, Rev1 BRCT-null mice develop UV-induced squamous cell carcinomas faster than wild-type controls.

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This article is based on research published under:

DOI-LINK: 10.4061/2010/643857, Alternate LINK

Title: Translesion Synthesis Polymerases In The Prevention And Promotion Of Carcinogenesis

Subject: Molecular Biology

Journal: Journal of Nucleic Acids

Publisher: Hindawi Limited

Authors: L. Jay Stallons, W. Glenn Mcgregor

Published: 2010-01-01

Everything You Need To Know

What is translesion DNA synthesis (TLS) and how does it work to repair damaged DNA?

Translesion DNA synthesis (TLS) is a crucial DNA repair mechanism employed by cells to replicate DNA even when it contains unrepaired damage. It acts as a workaround when the replication fork encounters a roadblock caused by DNA damage, allowing the cell to bypass the damaged area. The process involves specialized enzymes, known as TLS polymerases, which incorporate nucleotides across from the damaged site and extend the DNA strand. This can either be error-free, using polymerases like DNA polymerase η (Pol η) to accurately copy past damage, or error-prone, using other polymerases that may introduce mutations during the bypass. Cells utilize TLS to avoid replication fork blockage and potentially prevent the formation of cytotoxic double-strand breaks (DSB).

What is the role of TLS polymerases, particularly DNA polymerase η (Pol η), in the context of DNA damage and cancer?

TLS polymerases are enzymes that play a critical role in translesion DNA synthesis (TLS). DNA polymerase η (Pol η) is a well-understood TLS polymerase, especially known for its role in error-free bypass of UV-induced DNA damage. Other TLS polymerases, such as Pol ι, Pol κ, REV1, and Pol ζ, have been studied as well. These polymerases are responsible for navigating past DNA damage, allowing DNA replication to continue. While Pol η can facilitate error-free repair, other TLS polymerases can be error-prone. The involvement of these enzymes is a key point of investigation in cancer, as they are involved in the process of mutation by environmental agents. Understanding their functions is important for potentially developing targeted therapies.

How can translesion DNA synthesis (TLS) both prevent and promote cancer development?

Translesion DNA synthesis (TLS) exhibits a dual nature in cancer. It can prevent cancer by enabling cells to bypass DNA damage, such as that induced by UV radiation, thus preventing replication fork blockage and potentially reducing the risk of cell death. However, the same mechanism can also promote cancer. This happens when TLS results in the introduction of mutations during the bypass of damaged DNA. When the process is error-prone, and utilizes other polymerases, it can lead to changes in proto-oncogenes or tumor suppressor genes, which can drive the multistep process of tumorigenesis and contribute to cancer development. The decision between error-free repair, recombination, or error-prone TLS is governed by the molecular switch PCNA (proliferating cell nuclear antigen).

What are the key differences between error-free and error-prone TLS, and what are their implications?

Error-free TLS utilizes specialized polymerases like DNA polymerase η (Pol η) to accurately copy past DNA damage, ensuring minimal mutations. This is crucial for preventing genomic instability and, in effect, can help prevent cancer. Error-prone TLS, on the other hand, uses other polymerases that may introduce mutations during the bypass process. This can lead to alterations in genes and contribute to the development of cancer. The choice between error-free or error-prone TLS or another DNA repair mechanism such as recombination is regulated by the molecular switch PCNA (proliferating cell nuclear antigen). The type of TLS employed has profound implications for cancer risk, as error-free TLS protects against mutations, while error-prone TLS can promote them, impacting the function of proto-oncogenes and tumor suppressor genes.

How does the study of TLS, including the use of knockout mouse models, contribute to understanding and potentially treating cancer?

Studying translesion DNA synthesis (TLS) is vital to understanding cancer. Examining mice and humans with altered expression of TLS polymerases helps researchers understand how these enzymes affect cancer induced by environmental agents. For instance, the study of XP variant patients, who lack DNA polymerase η, demonstrates the importance of TLS in preventing UV-induced skin cancers. Additionally, the use of knockout mouse models, where specific TLS polymerases are absent or altered, provides insights into their role in carcinogenesis. This research can reveal how different TLS polymerases influence the development and progression of cancer. Such understanding can lead to the development of targeted therapies that manipulate TLS to either enhance DNA repair and prevent mutations or inhibit TLS to slow tumor growth.