英国苏塞克斯大学Ulrich Rass研究组揭示了DNA2通过限制重组重新启动的复制来促进生长。相关论文于2025年9月3日发表于国际顶尖学术期刊《自然》杂志上。

在这里，课题组研究人员以酵母和人类细胞为主题，证明了DNA2抑制同源体重组、重新启动的复制和在停滞的DNA复制分叉处的检查点激活。在细胞周期的G2期，DNA的合成和RPA结合的单链DNA的构建与重组依赖性DNA的合成有关。因此，DNA2剥夺触发DNA损伤检查点，并总是导致ATR–p21依赖性细胞周期在有丝分裂前退出。这些发现解释了为什么DNA2对细胞增殖至关重要，并揭示了限制重组的复制叉加工对于避免细胞衰老是必不可少的。在Seckel综合征患者衍生的DNA2低形态或部分降解表达后，随机进入衰老会抑制细胞的增殖潜力，这为解释DNA2相关的原始侏儒症疾病的整体生长失败提供了一个概念框架。

据了解，核酸酶解旋酶DNA2是一种多功能的基因组看护者，对从酵母到人类的一系列生物的细胞增殖至关重要。双等位基因DNA2突变降低了DNA2浓度，影响了一系列原始侏儒症，包括Seckel和Rothmund–Thomson相关综合征。相比之下，癌细胞经常表达高浓度的DNA2。在缺乏DNA2的情况下阻止细胞增殖的机制和DNA2相关疾病的分子病因学仍不清楚。

附：英文原文

Title: DNA2 enables growth by restricting recombination-restarted replication

Author: Hudson, Jessica J. R., Appanah, Rowin, Jones, David, Davidson, Kathryn, Budden, Alice M., Vaitsiankova, Alina, Chan, Kok-Lung, Caldecott, Keith W., Carr, Antony M., Rass, Ulrich

Issue&Volume: 2025-09-03

Abstract: Nuclease–helicase DNA2 is a multifunctional genome caretaker that is essential for cell proliferation in a range of organisms, from yeast to human1,2,3,4. Bi-allelic DNA2 mutations that reduce DNA2 concentrations cause a spectrum of primordial dwarfism disorders, including Seckel and Rothmund–Thomson-related syndromes5,6,7. By contrast, cancer cells frequently express high concentrations of DNA2 (refs.8,9,10,11). The mechanism that precludes cell proliferation in the absence of DNA2 and the molecular aetiology of DNA2-linked diseases remain elusive. Here we used yeast and human cells to demonstrate that DNA2 suppresses homologous recombination-restarted replication and checkpoint activation at stalled DNA replication forks. Loss of this control mechanism upon degradation of DNA2 in human cells causes recombination-dependent DNA synthesis and build-up of RPA-bound single-stranded DNA in the G2 phase of the cell cycle. Consequently, DNA2 deprivation triggers the DNA damage checkpoint and invariably leads to ATR–p21-dependent cell-cycle exit before mitosis. These findings explain why DNA2 is essential for cell proliferation and reveal that replication fork processing to restrict recombination is indispensable for avoiding cellular senescence. Stochastic entry into senescence stifles the proliferative potential of cells following the expression of a Seckel syndrome patient-derived DNA2 hypomorph or partial degradation of DNA2, providing a conceptual framework to explain global growth failure in DNA2-linked primordial dwarfism disorders.

DOI: 10.1038/s41586-025-09470-5

Source: https://www.nature.com/articles/s41586-025-09470-5