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Updated: Apr 4, 2026

Visualizing and Quantifying Endonuclease-Based Site-Specific DNA Damage
Published on: August 21, 2021
Mechanism of DNA damage tolerance
1Xin Bi, Department of Biology, University of Rochester, Rochester, NY 14627, United States.
Abstract:
DNA damage may compromise genome integrity and lead to cell death. Cells have evolved a variety of processes to respond to DNA damage including damage repair and tolerance mechanisms, as well as damage checkpoints. The DNA damage tolerance (DDT) pathway promotes the bypass of single-stranded DNA lesions encountered by DNA polymerases during DNA replication. This prevents the stalling of DNA replication. Two mechanistically distinct DDT branches have been characterized. One is translesion synthesis (TLS) in which a replicative DNA polymerase is temporarily replaced by a specialized TLS polymerase that has the ability to replicate across DNA lesions. TLS is mechanistically simple and straightforward, but it is intrinsically error-prone. The other is the error-free template switching (TS) mechanism in which the stalled nascent strand switches from the damaged template to the undamaged newly synthesized sister strand for extension past the lesion. Error-free TS is a complex but preferable process for bypassing DNA lesions. However, our current understanding of this pathway is sketchy. An increasing number of factors are being found to participate or regulate this important mechanism, which is the focus of this editorial.
Insights
DNA damage tolerance (DDT) bypasses DNA replication lesions. This editorial focuses on the error-free template switching (TS) mechanism, a complex but preferable pathway for maintaining genome integrity.
Area of Science:
- Molecular Biology
- Genetics
- Cell Biology
Background:
- DNA damage can lead to genome instability and cell death.
- Cells possess repair, tolerance, and checkpoint mechanisms to respond to DNA damage.
- The DNA damage tolerance (DDT) pathway bypasses DNA lesions during replication to prevent fork stalling.
Purpose of the Study:
- To provide an overview of the DNA damage tolerance (DDT) pathway.
- To highlight the translesion synthesis (TLS) and template switching (TS) branches of DDT.
- To focus on the less understood, error-free template switching (TS) mechanism.
Main Methods:
- Review of existing literature on DNA damage tolerance pathways.
- Comparison of the mechanisms of translesion synthesis (TLS) and template switching (TS).
- Discussion of the factors involved in regulating the template switching (TS) pathway.
Main Results:
- Two distinct DDT branches exist: TLS and TS.
- TLS is error-prone, while TS is error-free but complex.
- The understanding of the TS pathway is limited but growing.
Conclusions:
- The template switching (TS) mechanism is a crucial, error-free pathway for bypassing DNA lesions.
- Further research is needed to fully elucidate the regulation and factors involved in TS.
- Understanding DDT pathways is vital for maintaining genome integrity.
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