Beyond Short Microhomologies: Mismatch-Compatible Pol θ-Mediated DNA Damage Repair

Authors

Yuzhen Li
Richard D Wood

Language

English

Publication Date

3-1-2026

Journal

Bioessays

DOI

10.1002/bies.70129

PMID

41879469

PMCID

PMC13015775

PubMedCentral® Posted Date

3-25-2026

PubMedCentral® Full Text Version

Post-print

Abstract

DNA polymerase θ (Pol θ)-mediated end-joining (TMEJ), one of several pathways for repairing DNA double-strand breaks, is traditionally thought to initiate via anchoring at short, consecutive, and perfectly matched microhomologies (MHs). Emerging evidence indicates that Pol θ can utilize MHs containing mismatches both in vitro and in vivo. This revised definition of MH provides a mechanistic explanation for a broader spectrum of Pol θ-dependent repair outcomes. Here, we summarize recent findings on the revised definition of MHs utilized by Pol θ, assess the applicability of this concept across species, and compare TMEJ with other (micro)hom(e)ology-mediated repair pathways. We explore how mismatch-containing MHs expand Pol θ-associated mutational signatures and provide a framework for future studies on Pol θ's role in DNA repair and cancer biology.

Keywords

DNA-Directed DNA Polymerase, Humans, DNA Polymerase theta, Animals, DNA Repair, DNA End-Joining Repair, DNA Breaks, Double-Stranded, DNA Damage, DNA Mismatch Repair, DNA polymerase θ (Pol θ), microhomology, mismatches, mutational signatures, TMEJ

Published Open-Access

yes

Recommended Citation

Yuzhen Li and Richard D Wood, "Beyond Short Microhomologies: Mismatch-Compatible Pol θ-Mediated DNA Damage Repair" (2026). Faculty, Staff and Student Publications. 6801.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6801