Molecular Control of Replication Fork Speed: dNTP Availability, Phosphorylation, PARylation, and UFMylation

IF 3.3 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

BioEssays Pub Date : 2026-10-07 DOI:10.1002/bies.70185

Zheng Li, Akira Shinohara, Yisui Xia, Xingzhi Xu, Shunichi Takeda

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引用次数: 0

Abstract

The regulation of replication fork (RF) speed is essential for faithful genome duplication and the maintenance of genome stability, and its dysregulation contributes to carcinogenesis and developmental disorders. Although many anticancer therapies perturb DNA replication, the molecular mechanisms by which RF speed is controlled remain incompletely understood. A major limitation has been the frequent omission of direct measurements of cellular deoxynucleotide triphosphate (dNTP) pools, despite their strong and immediate influence on DNA polymerase kinetics. In this review, we first summarize how dNTP availability constrains RF progression under physiological and stress conditions. We then discuss how anticancer agents targeting DNA replication modulate RF speed through phosphorylation-dependent signaling pathways. Finally, we examine emerging roles of PARylation and UFMylation as rapid, replisome-centered regulatory mechanisms that fine-tune fork progression and stability, and we highlight their clinical implications, including a mechanistic link between aberrant replisome regulation and microcephalic primordial dwarfism.

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分子控制的复制叉速度：dNTP可用性，磷酸化，PARylation，和UFMylation。

复制叉（RF）速度的调节对于基因组的忠实复制和基因组稳定性的维持至关重要，其失调有助于致癌和发育障碍。尽管许多抗癌疗法干扰DNA复制，但控制射频速度的分子机制仍未完全了解。一个主要的限制是经常遗漏直接测量细胞脱氧核苷酸三磷酸（dNTP）池，尽管它们对DNA聚合酶动力学有强烈和直接的影响。在这篇综述中，我们首先总结了dNTP的可用性如何在生理和应激条件下限制RF的进展。然后，我们讨论了靶向DNA复制的抗癌药物如何通过磷酸化依赖的信号通路调节RF速度。最后，我们研究了PARylation和UFMylation作为快速的、以复制体为中心的调控机制，微调分叉的进展和稳定性，并强调了它们的临床意义，包括异常的复制体调控与小头畸形原始侏儒症之间的机制联系。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

BioEssays 生物-生化与分子生物学

CiteScore

7.30

自引率

2.50%

发文量

167

审稿时长

4-8 weeks

期刊介绍： molecular – cellular – biomedical – physiology – translational research – systems - hypotheses encouraged BioEssays is a peer-reviewed, review-and-discussion journal. Our aims are to publish novel insights, forward-looking reviews and commentaries in contemporary biology with a molecular, genetic, cellular, or physiological dimension, and serve as a discussion forum for new ideas in these areas. An additional goal is to encourage transdisciplinarity and integrative biology in the context of organismal studies, systems approaches, through to ecosystems, where appropriate.