Is non-homologous end-joining really an inherently error-prone process?

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• DNA double-strand breaks (DSBs) are critical DNA lesions that can lead to genomic instability.
• Non-homologous end-joining (NHEJ) is a major pathway for repairing DSBs.
• NHEJ was traditionally considered error-prone, but recent evidence suggests intrinsic precision.

Purpose of the Study:

• To re-evaluate the accuracy of the canonical NHEJ (C-NHEJ) pathway.
• To identify factors contributing to the perceived error-proneness of NHEJ.
• To explore the implications of C-NHEJ's adaptability in various biological contexts.

Main Methods:

• Analysis of NHEJ mechanisms across different organisms.
• Review of existing data on DSB repair pathways.
• Comparative assessment of C-NHEJ and alternative end-joining processes.

Main Results:

• The apparent errors in NHEJ are often due to an alternative, error-prone end-joining pathway.
• Canonical C-NHEJ is adaptable to imperfect DNA ends and processes incompatible ends.
• The fidelity of C-NHEJ is determined by the DNA end structure, not the repair proteins.

Conclusions:

• C-NHEJ is a conservative yet adaptable pathway crucial for genomic integrity.
• The versatility of C-NHEJ supports immune repertoire development and radiation resistance.
• Understanding C-NHEJ accuracy is vital for targeted genome manipulation technologies.