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Translesion DNA polymerases
Myron F Goodman1, Roger Woodgate
1Department of Biological Sciences and Department of Chemistry, University of Southern California, University Park, Los Angeles, California 90089-2910.
Abstract:
Living cells are continually exposed to DNA-damaging agents that threaten their genomic integrity. Although DNA repair processes rapidly target the damaged DNA for repair, some lesions nevertheless persist and block genome duplication by the cell's replicase. To avoid the deleterious consequence of a stalled replication fork, cells use specialized polymerases to traverse the damage. This process, termed "translesion DNA synthesis" (TLS), affords the cell additional time to repair the damage before the replicase returns to complete genome duplication. In many cases, this damage-tolerance mechanism is error-prone, and cell survival is often associated with an increased risk of mutagenesis and carcinogenesis. Despite being tightly regulated by a variety of transcriptional and posttranslational controls, the low-fidelity TLS polymerases also gain access to undamaged DNA where their inaccurate synthesis may actually be beneficial for genetic diversity and evolutionary fitness.
Insights
Cells use translesion DNA synthesis (TLS) to bypass DNA damage during replication. While error-prone TLS aids survival, it can increase mutation risk but also promote genetic diversity.
Area of Science:
- Molecular Biology
- Genetics
- Cell Biology
Background:
- Living cells face constant DNA damage threats to genomic integrity.
- DNA repair mechanisms address lesions, but some persist, stalling DNA replication.
- Stalled replication forks trigger specialized polymerases for translesion DNA synthesis (TLS).
Purpose of the Study:
- To explain the role of translesion DNA synthesis (TLS) in DNA damage tolerance.
- To investigate the implications of TLS in cell survival, mutagenesis, and genetic diversity.
Main Methods:
- Review of cellular DNA repair and replication processes.
- Analysis of the function of specialized TLS polymerases.
- Examination of the regulation and consequences of TLS.
Main Results:
- TLS allows replication to proceed past DNA lesions, providing time for repair.
- TLS is often error-prone, linking cell survival to increased mutagenesis and cancer risk.
- Regulated TLS polymerases can access undamaged DNA, potentially benefiting genetic diversity.
Conclusions:
- Translesion DNA synthesis is a critical, albeit risky, DNA damage tolerance mechanism.
- The fidelity of TLS polymerases impacts both mutagenesis and evolutionary adaptation.
- Understanding TLS is crucial for comprehending genome stability and disease development.
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