How Cells Prevent Replication Fork Collapse Caused by UV-Induced DNA Damage: The Role of Lesion Bypass

Ultraviolet (UV) radiation is a common environmental mutagen that induces DNA damage, primarily in the form of pyrimidine dimers. These lesions distort the DNA helix and pose significant challenges to the advancing replication forks during DNA synthesis. When replication forks encounter UV-induced DNA damage, they often stall, risking fork collapse and genomic instability. To maintain replication progression and genome integrity, cells employ specialized mechanisms to bypass these lesions.

UV-Induced DNA Damage and Replication Fork Stalling

• Pyrimidine dimers, such as cyclobutane pyrimidine dimers (CPDs), are the primary UV-induced lesions.

• These bulky lesions block the replicative DNA polymerases, causing the replication machinery to stall.

• Prolonged stalling can lead to replication fork collapse, resulting in double-strand breaks and chromosomal abnormalities.

Cellular Strategy to Avoid Replication Fork Collapse: Lesion Bypass

To prevent fork collapse, cells utilize lesion bypass mechanisms, also known as translesion synthesis (TLS) or damage tolerance pathways, which allow replication to continue past DNA lesions without immediately repairing them.

• Lesion bypass involves specialized TLS DNA polymerases that can synthesize DNA across damaged templates.

• These polymerases have flexible active sites that accommodate distorted DNA and insert nucleotides opposite lesions.

• Although TLS polymerases are error-prone, their activity is crucial for preventing replication fork collapse and maintaining cell viability.

Why Other Repair Mechanisms Are Not Suitable for Immediate Fork Restart

1. Non-Homologous End Joining (NHEJ):

   • Repairs double-strand breaks by directly ligating DNA ends without homology.

   • Not involved in bypassing replication-blocking lesions or preventing fork stalling.

2. Mismatch Repair (MMR):

   • Corrects base mismatches and small insertion/deletion loops post-replication.

   • Does not bypass bulky lesions or restart stalled forks.

3. Base Excision Repair (BER):

   • Repairs small, non-helix-distorting base lesions like oxidized or alkylated bases.

   • Not effective against bulky UV-induced lesions blocking replication.

Summary Table

Correct Answer

(2) Lesion bypass

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• DNA damage-induced replication fork restart

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Conclusion

When UV-induced DNA damage causes replication forks to stall, cells rely on lesion bypass mechanisms, particularly translesion synthesis, to allow replication to continue past the lesions. This prevents fork collapse and preserves genomic integrity. Other repair pathways like non-homologous end joining, mismatch repair, and base excision repair do not directly facilitate replication fork restart in the presence of bulky UV lesions.

Correct answer: (2) lesion bypass