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

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).

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.

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).

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.

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.