Translesion DNA Synthesis Mechanisms in Human Cells

Translesion DNA synthesis (TLS) is a damage-tolerance pathway that enables replication to proceed past lesions that would otherwise stall high-fidelity replicative polymerases. In human cells, specialised Y-family polymerases—most notably DNA polymerase η (Pol η), DNA polymerase ι (Pol ι) and Rev1—are recruited to stalled replication forks via interactions with proliferating cell nuclear antigen (PCNA) and ubiquitin signalling. These enzymes possess flexible active sites that accommodate distorted templates, allowing them to insert nucleotides opposite bulky adducts, cross-links or UV-induced lesions. Although inherently error-prone, TLS polymerases are carefully regulated through post-translational modifications and protein-protein interactions to minimise mutagenesis while preserving genome integrity. Emerging evidence reveals that TLS factors also participate in base excision repair and coordinate with chromatin regulators, underscoring their multifaceted roles in DNA damage response and cellular homeostasis.

Research from Nature Portfolio

Recent studies have elucidated novel regulatory and enzymatic features of human DNA polymerase ι. One work identified key amino acid residues within Pol ι that underpin its deoxyribose phosphate lyase activity, revealing the involvement of N-terminal and finger domains in base excision repair. Mutagenesis of residues Q59, K60 and K207 markedly reduced dRP-lyase function and Schiff-base intermediate formation, thereby illuminating the structural basis of Pol ι’s dual function in lesion bypass and strand incision. Another investigation demonstrated that Pol ι undergoes acetylation at a principal lysine in its Rev1-interacting region in response to SN2 alkylating damage. This modification, mediated by p300 acetyltransferase, is specific to Pol ι among Y-family polymerases and augments under alkylating stress, suggesting acetylation as a dynamic modulator of TLS specificity.

Translesion DNA Synthesis Mechanisms in Human Cells publication trend

The graph below shows the total number of articles in translesion dna synthesis mechanisms in human cells across all publications each year (not limited to Nature Index journals).

Technical terms

Translesion DNA synthesis (TLS): A DNA damage tolerance process in which specialised polymerases bypass lesions that stall replicative enzymes.

DNA polymerase ι (Pol ι): A Y-family, low-fidelity enzyme that performs lesion bypass and possesses deoxyribose phosphate lyase activity.

DNA polymerase η (Pol η): A Y-family polymerase capable of accurately replicating past UV-induced thymine dimers.

dRP-lyase activity: The ability of a polymerase to cleave deoxyribose phosphate groups during base excision repair.

Acetylation: A post-translational modification involving the addition of an acetyl group to lysine residues, regulating protein function.

cis-syn thymine–thymine dimer: A covalent lesion formed between adjacent thymine bases under UV irradiation that distorts DNA helix.

References

1. DNA polymerase iota promotes EMT and metastasis of esophageal squamous cell carcinoma by interacting with USP7 to stabilize HIF-1α. Cell Death & Disease (2024).
2. Increased Catalytic Activity and Altered Fidelity of Human DNA Polymerase ι in the Presence of Manganese*. Journal of Biological Chemistry (2007).
3. Fidelity of Human DNA Polymerase η*. Journal of Biological Chemistry (2000).
4. Proliferating Cell Nuclear Antigen-dependent Coordination of the Biological Functions of Human DNA Polymerase ι*. Journal of Biological Chemistry (2004).
5. Identification of amino acid residues involved in the dRP-lyase activity of human Pol ι. Scientific Reports (2017).
6. DNA polymerase ι is acetylated in response to SN2 alkylating agents. Scientific Reports (2019).