Transcription-replication conflicts: A regulated interface in genome maintenance

Wang Qiong; He Jiacheng; Duan Zibo; Huang Jinzhou

doi:10.70401/acrt.2026.0042

Transcription-replication conflicts: A regulated interface in genome maintenance

Qiong Wang

Jiacheng He

Zibo Duan

Jinzhou Huang

Affiliation +

*Correspondence to: Jinzhou Huang, Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou 310000, Zhejiang, China. E-mail: huangjinzhou@him.cas.cn

Ageing Cancer Res Treat. 2027;4:202634. 10.70401/acrt.2026.0042

Received: July 31, 2026Accepted: September 17, 2026Published: September 18, 2026

This article belongs to the Special lssue Replication Stress Responses and Genome Stability: Mechanisms, Regulation, and Disease Implications

This manuscript is made available in its unedited form to allow early access to the reported findings. Further editing will be completed before final publication. As such, the content may include errors, and standard legal disclaimers are applicable.

Abstract

DNA replication and transcription operate on the same chromatin template and inevitably interfere with one another, giving rise to transcription-replication conflicts (TRCs), an important endogenous source of replication stress and genome instability. Although head-on (HO) conflicts are generally more disruptive than co-directional (CD) encounters, orientation alone does not determine the outcome. Gene architecture, transcriptional activity, replication timing, chromatin environment, DNA topology, and R-loop dynamics can all influence whether an approaching replication fork pauses, collapses, or traverses a transcribed region. Recent single-molecule, genomic, and biochemical studies further suggest that some CD encounters can be traversed under favorable topological and transcriptional conditions, although the mechanisms that permit such bypass and their broader biological significance remain incompletely understood. Here, we discuss TRC control within an operational framework comprising prevention, resolution, tolerance, and recovery. We examine how cells coordinate replication and transcription in space and time, regulate R-loop formation and turnover, protect or remodel challenged forks and chromatin, and modify or remove transcription complexes at conflict sites. We also consider how emerging single-molecule and multi-omic approaches can distinguish transient fork pausing from persistent pathological conflicts. Finally, we discuss the contributions of TRCs to cancer-associated chromosomal instability, cellular senescence, and neurodegenerative disease, and highlight the questions that must be resolved to understand how cells preserve genome integrity when replication and transcription compete for the same DNA template.

Keywords

Transcription–replication conflicts, replication stress, genome stability

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Wang Q, He J, Duan Z, Huang J. Transcription-replication conflicts: A regulated interface in genome maintenance. Ageing Cancer Res Treat. 2027;4:202634. https://doi.org/10.70401/acrt.2026.0042