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

TL;DR

This paper explores how DNA polymerase θ repairs DNA breaks using mismatch-compatible microhomologies, expanding our understanding of its role in DNA repair and cancer.

Contribution

The paper introduces a revised definition of microhomologies used by Pol θ, including mismatch-compatible sequences.

Findings

Pol θ can utilize mismatch-compatible microhomologies for DNA repair.

The revised definition of microhomologies is applicable across species.

Mismatch-compatible microhomologies expand Pol θ-associated mutational signatures.

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.

Pol θ is traditionally thought to use a short, perfectly matched microhomology (MH) to initiate end‐joining repair of a DNA double‐strand break. Emerging evidence indicates that Pol θ generally utilizes mismatch‐compatible longer microhomologies. This revised definition of MH is applicable across species and broadens the definition of Pol θ‐associated mutational signatures.

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