Modernizing the nonhomologous end-joining repertoire: alternative and classical NHEJ share the stage

Area of Science:

• Molecular Biology
• Genetics
• Cell Biology

Background:

• DNA double-strand breaks (DSBs) are critical DNA lesions impacting genomic stability.
• DSB misrepair, particularly via nonhomologous end-joining (NHEJ), can lead to oncogenic transformation and genome scrambling.
• Canonical repair pathways include homologous recombination (HR) and classical NHEJ (cNHEJ).

Purpose of the Study:

• To review the mechanisms of cNHEJ and alternative NHEJ (aNHEJ) pathways.
• To explore the interplay between these DSB repair pathways and the DNA damage response (DDR).
• To discuss the regulatory mechanisms governing DSB repair pathway choice and clinical applications of NHEJ inhibitors.

Main Methods:

• Literature review of mechanisms governing DSB repair.
• Analysis of the DNA damage response (DDR) pathways.
• Review of clinical applications and inhibitors targeting NHEJ.

Main Results:

• Identified alternative NHEJ (aNHEJ) as a distinct, error-prone pathway operating alongside cNHEJ.
• Highlighted aNHEJ's role in catalyzing genome rearrangements and oncogenic transformation.
• Detailed the DDR's influence on selecting between HR, cNHEJ, and aNHEJ for DSB repair.

Conclusions:

• Understanding cNHEJ and aNHEJ mechanisms is vital for comprehending genome stability and disease.
• The DDR orchestrates the choice of DSB repair pathway, impacting cellular fate.
• Targeting NHEJ pathways offers potential therapeutic strategies for cancer treatment.