Polymerases η, ι, and κ: Key Enzymes in Translesion Synthesis and DNA Damage Tolerance

Polymerases η, ι, and κ: Key Enzymes in Translesion Synthesis and DNA Damage Tolerance (Extended Overview)

Polymerases η (Pol η), ι (Pol ι), and κ (Pol κ) belong to Family Y of DNA polymerases, which is a subset of polymerases responsible for translesion synthesis (TLS). These polymerases are particularly important for DNA damage tolerance, enabling the replication machinery to bypass lesions or damage in the DNA template that would otherwise stall the replication fork. TLS is a critical mechanism to maintain DNA replication in the presence of various DNA lesions, but it comes with the trade-off of increased error rates and reduced fidelity. While Pol η, Pol ι, and Pol κ contribute to the repair of damaged DNA, they do so with varying degrees of accuracy and specificity.

Credit of Picture: cell.com

1. Polymerase η (Pol η): The UV Damage Specialist

Polymerase η is one of the most well-characterized translesion synthesis polymerases, particularly in its role in bypassing DNA lesions induced by ultraviolet (UV) radiation, a major environmental mutagen. UV radiation causes the formation of pyrimidine dimers (most commonly thymine-thymine dimers) in DNA. These dimers create a structural distortion in the DNA, which can halt the progression of the replicative polymerases, such as Pol δ or Pol ε, that are responsible for synthesizing the DNA strand during replication.

Pol η is specialized for accurate translesion synthesis across these UV-induced lesions. Its role involves inserting the correct bases opposite the dimerized pyrimidines. The specificity of Pol η is noteworthy because, unlike other TLS polymerases, it has relatively high fidelity when bypassing UV-induced lesions. This is due to its ability to properly insert adenine opposite a thymine dimer, a process that significantly reduces the mutation rate associated with UV damage. Importantly, Pol η can carry out translesion synthesis without causing the significant mutagenic effects that other polymerases in the TLS family might induce.

Pol η’s function is particularly significant in xeroderma pigmentosum (XP), a genetic disorder characterized by hypersensitivity to UV radiation and an increased risk of skin cancers. Mutations in the gene encoding Pol η lead to the loss of the enzyme’s ability to accurately bypass UV-induced lesions, exacerbating the effects of UV damage.

Key Points about Pol η:

• Primary function: Bypasses UV-induced pyrimidine dimers (such as thymine-thymine dimers) with relatively high accuracy.

• Repair mechanism: Ensures correct base insertion opposite UV-induced lesions, maintaining low mutation rates during translesion synthesis.

• Significance: Pol η is essential for efficient DNA repair in response to UV radiation; defects in Pol η are associated with xeroderma pigmentosum and an increased risk of UV-induced cancers.

• Accuracy: One of the most accurate TLS polymerases, preventing excessive mutagenesis from UV-induced DNA damage.

2. Polymerase ι (Pol ι): A High Fidelity but Error-Prone Enzyme

Polymerase ι is another member of the translesion synthesis polymerase family, but it has distinct characteristics compared to Pol η. Unlike Pol η, Pol ι is known for its high error-prone activity, meaning that while it is capable of bypassing lesions during DNA replication, it does so with significantly lower fidelity, leading to increased mutation rates.

Pol ι is particularly involved in bypassing lesions caused by alkylation damage and oxidative stress. These types of damage can result in DNA base modifications such as 8-oxoguanine or alkylated bases, which distort the DNA structure and impede normal DNA replication. Pol ι is able to insert bases opposite these lesions, though it is prone to making errors, often incorporating incorrect nucleotides during the bypass process. This error-prone characteristic of Pol ι, while essential for allowing replication to continue in the presence of DNA damage, can also contribute to genomic instability if lesions are not repaired properly.

The exact mechanisms of Pol ι are still under investigation, but it is thought to function primarily in a low-fidelity bypass context where rapid DNA synthesis is more important than maintaining high fidelity, such as in response to oxidative damage or during replication stress.

Key Points about Pol ι:

• Primary function: Bypasses various DNA lesions, including alkylation damage and oxidative lesions, though with high error rates.

• Repair mechanism: Known for error-prone activity, Pol ι often inserts incorrect bases opposite lesions during translesion synthesis.

• Mutagenic potential: Its high error rate contributes to genetic instability, particularly in response to oxidative and alkylating damage.

• Role in DNA damage tolerance: Essential for ensuring that DNA replication can continue in the presence of lesions that would otherwise stall the replication fork, despite its potential for inducing mutations.

3. Polymerase κ (Pol κ): A Versatile Lesion Bypass Enzyme

Polymerase κ is a less understood but important member of the translesion synthesis polymerase family. It has been implicated in the bypass of a variety of DNA lesions, including those induced by ionizing radiation, oxidative stress, and alkylation damage. While it is still under extensive investigation, several studies suggest that Pol κ plays a key role in the repair of DNA double-strand breaks (DSBs) and interstrand cross-links, which are types of damage that pose significant challenges to DNA replication.

Unlike Pol η, which is specialized for UV-induced damage, Pol κ is more versatile, being able to handle a wider array of DNA lesions. This flexibility includes bypassing guanine-guanine cross-links, a common result of oxidative damage or alkylation, as well as other types of base modifications. However, much like Pol ι, Pol κ is known to be prone to errors, especially in its bypass of complex lesions. It often inserts bases opposite bulky lesions or distortions in the DNA that the replicative polymerases are unable to replicate across.

Despite its error-prone nature, Pol κ is essential in cases where the replication fork is stalled due to such lesions, providing a means for the cell to continue replication. Its ability to extend and insert nucleotides across DNA lesions is indispensable for maintaining genome integrity in the face of certain types of damage, though it comes at the cost of introducing potential mutations.

Key Points about Pol κ:

• Primary function: Bypasses a wide range of DNA lesions, including those caused by ionizing radiation, alkylation, and oxidative damage.

• Repair mechanism: Capable of inserting nucleotides opposite complex DNA lesions such as guanine-guanine cross-links and other base modifications.

• Error-prone: Like Pol ι, Pol κ is prone to inserting incorrect bases during translesion synthesis, which can lead to mutations and genomic instability.

• Flexibility: Pol κ is more versatile than Pol η, functioning in response to a broader range of DNA damage types, including oxidative and radiation-induced damage.

Translesion Synthesis: A Double-Edged Sword

The process of translesion synthesis is essential for bypassing lesions that would otherwise cause replication forks to stall, such as those induced by UV radiation, oxidative damage, or chemical mutagens. However, the polymerases responsible for TLS, including Pol η, Pol ι, and Pol κ, are prone to errors during DNA synthesis. This error-prone characteristic is part of the reason why TLS polymerases are sometimes referred to as “low-fidelity” polymerases. They prioritize the continuation of DNA replication over maintaining perfect fidelity, leading to the incorporation of incorrect nucleotides at the lesion site.

The activation of these polymerases typically occurs when the replicative DNA polymerases (such as Pol δ and Pol ε) encounter a lesion that stalls the replication fork. The stalled replicative polymerases recruit TLS polymerases to the site of the lesion, allowing DNA synthesis to continue. However, the tolerance of DNA damage comes at the cost of an increased potential for mutagenesis. The result is a trade-off between allowing DNA replication to continue and introducing mutations into the genome, which can sometimes lead to carcinogenesis or other genomic instabilities.

Key Features of Translesion Synthesis Polymerases (Pol η, Pol ι, and Pol κ):

• Activation: TLS polymerases are activated when replicative polymerases stall at a lesion, allowing replication to continue despite the damage.

• Error-prone nature: These polymerases often incorporate incorrect nucleotides opposite lesions, contributing to mutations and genomic instability.

• Role in DNA damage tolerance: Essential for ensuring that DNA replication continues in the face of DNA damage, though this can come with an increased risk of mutagenesis.

• Specialization: Each TLS polymerase has its own set of preferred lesions and types of DNA damage it is specialized to bypass (e.g., Pol η for UV-induced lesions, Pol ι for alkylation and oxidative damage, and Pol κ for a broader range of lesions).

Review Section

Polymerases η, ι, and κ are essential for translesion synthesis, a DNA repair mechanism that allows the replication fork to bypass a variety of DNA lesions that would otherwise impede replication. Each polymerase has its own strengths and limitations:

• Pol η is highly specialized for UV-induced damage and performs relatively accurate translesion synthesis.
• Pol ι is highly error-prone and bypasses lesions caused by oxidative stress and alkylation damage, contributing to mutagenesis.
• Pol κ is versatile in handling a wide array of DNA lesions, though it is also prone to errors.

While these polymerases are indispensable for DNA damage tolerance, their error-prone nature introduces challenges, particularly in the maintenance of genomic stability. Understanding how these polymerases function in translesion synthesis is crucial for comprehending how cells cope with DNA damage and for assessing their roles in diseases such as cancer, where mutagenic TLS may contribute to tumorigenesis.