How Translesion Synthesis (TLS) DNA Polymerases Reduce Replicative Fidelity by 100-Fold

DNA replication fidelity is critical for genome stability. However, when DNA damage blocks replicative polymerases, cells employ specialized DNA polymerases known as translesion synthesis (TLS) polymerases to bypass lesions and allow replication to continue. While TLS polymerases enable replication past damaged sites, they do so at the cost of greatly reduced fidelity.

What Are TLS DNA Polymerases?

TLS polymerases belong mainly to the Y-family (e.g., Pol η, Pol κ, Pol ι) and some B-family members (e.g., Pol ζ). They have:

• A more spacious active site allowing accommodation of distorted or damaged DNA templates.

• Lack of 3′→5′ exonuclease proofreading activity.

• Lower nucleotide selectivity, leading to increased misincorporation rates.

Fidelity Reduction by TLS Polymerases

• TLS polymerases can reduce replication fidelity by a factor of approximately 10² (100-fold) compared to replicative polymerases.

• This reduction arises because TLS polymerases insert nucleotides opposite lesions with less discrimination and extend mismatched primer termini more readily.

• For example, Pol ζ is known to generate base substitutions and insertions/deletions at relatively high rates during lesion bypass.

Why Is Fidelity Reduced?

• The active site geometry of TLS polymerases is more flexible, allowing accommodation of bulky or distorted lesions but sacrificing base-pairing stringency.

• TLS polymerases lack proofreading exonuclease domains, so errors made during synthesis are not corrected.

• Cells tightly regulate TLS polymerase activity to minimize mutagenesis, restricting their action to damaged sites.

Comparison with Other DNA Repair Proteins

• AP endonuclease: Involved in base excision repair; it cleaves DNA near abasic sites but does not affect replication fidelity directly.

• ABC exonuclease: Generally involved in DNA degradation or processing, not directly linked to fidelity reduction during synthesis.

• DNA photolyase: Directly reverses UV-induced pyrimidine dimers without introducing errors, thus does not reduce fidelity.

Conclusion

The protein responsible for a ~100-fold reduction in replicative base selection fidelity during DNA synthesis repair is the TLS DNA polymerase. These specialized polymerases enable replication past DNA lesions but at the cost of increased mutation rates.

Correct Answer

(4) TLS DNA polymerase

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• Translesion synthesis DNA polymerase fidelity

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• AP endonuclease function

• DNA photolyase and direct repair

• DNA lesion bypass polymerases

• Error-prone DNA synthesis

The fidelity of replicative base selection can be reduced by a factor of 10²  when the repair of DNA synthesis involves
(1) AP endonuclease                (2) ABC exonuclease
(3) DNA photolyase                  (4) TLS DNA polymerase.

This explanation clarifies that TLS DNA polymerases are the key players in reducing replication fidelity during DNA synthesis repair, distinguishing them from other repair proteins.