Routing strand lesions during DNA replication: Coordination between single-strand break repair and double-strand break repair shapes lesion fate

Yang Yuexin; Wen Jihang; Wei Saisai; Shao Zhengping

doi:10.70401/acrt.2026.0041

Routing strand lesions during DNA replication: Coordination between single-strand break repair and double-strand break repair shapes lesion fate

Yuexin Yang

Jihang Wen

Saisai Wei

Zhengping Shao

1,3,*

Affiliation +

*Correspondence to: Zhengping Shao, Department of Pathology and Pathophysiology, and Department of Colorectal Surgery and Oncology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang, China; Zhejiang University Cancer Center, Hangzhou 310058, Zhejiang, China. E-mail: zhengping.shao@zju.edu.cn

Ageing Cancer Res Treat. 2027;4:202630. 10.70401/acrt.2026.0041

Received: July 01, 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 constantly faces obstacles that threaten genome stability. Faithful duplication requires replication forks to smoothly process template damage, chemical or topological blocks, and repair intermediates. Traditionally, replication-associated lesions are described by their initial structures (nicks, gaps, etc.). However, their S-phase identities are highly transitional: a template single-strand break (SSB) can become a one-ended double-strand break (DSB) upon fork arrival, a replication fork stalled by a template block can reverse, restart, or collapse, and a repriming event leaves a post-replicative single-stranded DNA (ssDNA) gap. The biological consequence of a lesion depends heavily on its structural transitions and how it is "routed" through distinct repair, bypass, or cleavage pathways. In this review, we shift our focus from static structural identities to dynamic lesion routing, emphasizing the coordination between SSB repair (SSBR) and DSB repair (DSBR). We first summarize the major sources of replication-associated strand lesions, and then discuss how strand lesions are managed across three processing windows: SSBR before fork encounter, the overlap zone in which gaps and stressed forks can be buffered without immediate DSB conversion, and broken-fork/DSBR-centered processing after DSB formation, including homologous recombination (HR)-mediated restart, break-induced replication (BIR)-like synthesis, or end joining. Depending on the routing network, lesion processing can result in accurate completion, delayed resolution or salvage, mutagenic completion, structural genome scars, or cytotoxic genome instability. Finally, we discuss how this dynamic framework refines our understanding of DNA damage response (DDR)-targeted cancer therapies, drug resistance, and treatment outcomes in different genetic or therapeutic contexts.

Keywords

DNA replication, single-strand break repair, double-strand break repair, ssDNA gap, replication fork restart, strand lesion routing

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Yang Y, Wen J, Wei S, Shao Z. Routing strand lesions during DNA replication: Coordination between single-strand break repair and double-strand break repair shapes lesion fate. Ageing Cancer Res Treat. 2027;4:202630. https://doi.org/10.70401/acrt.2026.0041