Zhu Tianyi, Tan Jing Zhi Anson, Zhang Lingrui, Huang He, Das Sooraj S, Cheng Flora, Padmanabhan Pranesh, Jones Mathew J K, Lee Mihwa, Lee Albert, Widagdo Jocelyn, Anggono Victor
Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, Faculty of Health, Medicine and Behavioural Sciences, The University of Queensland, Brisbane, Australia.
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, USA.
Nat Commun. 2025 Mar 25;16(1):2925. doi: 10.1038/s41467-025-58309-0.
Maintaining genomic integrity and faithful transmission of genetic information is essential for the survival and proliferation of cells and organisms. DNA damage, which threatens the integrity of the genome, is rapidly sensed and repaired by mechanisms collectively known as the DNA damage response. The RNA demethylase FTO has been implicated in this process; however, the underlying mechanism by which FTO regulates DNA repair remains unclear. Here, we use an unbiased quantitative proteomic approach to identify the proximal interactome of endogenous FTO protein. Our results demonstrate a direct interaction with the DNA damage sensor protein PARP1, which dissociates upon ultraviolet stimulation. FTO inhibits PARP1 catalytic activity and controls its clustering in the nucleolus. Loss of FTO enhances PARP1 enzymatic activity and the rate of PARP1 recruitment to DNA damage sites, accelerating DNA repair and promoting cell survival. Interestingly, FTO regulates PARP1 function and DNA damage response independent of its catalytic activity. We conclude that FTO is an endogenous negative regulator of PARP1 and the DNA damage response in cells beyond its role as an RNA demethylase.
维持基因组完整性和遗传信息的忠实传递对于细胞和生物体的生存与增殖至关重要。DNA损伤会威胁基因组的完整性，可通过统称为DNA损伤反应的机制迅速被感知并修复。RNA去甲基化酶FTO已被证明参与这一过程；然而，FTO调节DNA修复的潜在机制仍不清楚。在这里，我们使用一种无偏差的定量蛋白质组学方法来鉴定内源性FTO蛋白的近端相互作用组。我们的结果表明FTO与DNA损伤传感器蛋白PARP1直接相互作用，这种相互作用在紫外线刺激后会解离。FTO抑制PARP1的催化活性并控制其在核仁中的聚集。FTO的缺失增强了PARP1的酶活性以及PARP1募集到DNA损伤位点的速率，加速了DNA修复并促进了细胞存活。有趣的是，FTO调节PARP1功能和DNA损伤反应与其催化活性无关。我们得出结论，FTO是PARP1的内源性负调节因子，并且在细胞中作为RNA去甲基化酶之外，还参与DNA损伤反应。
