Department for BioMedical Research, Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland.
Department of Radiation Oncology, Inselspital, Bern University Hospital, Freiburgstrasse 8, 3008, Bern, Switzerland.
Oncogene. 2023 Jun;42(26):2113-2125. doi: 10.1038/s41388-023-02714-6. Epub 2023 May 15.
The DNA damage response (DDR) is intertwined with signaling pathways downstream of oncogenic receptor tyrosine kinases (RTKs). To drive research into the application of targeted therapies as radiosensitizers, a better understanding of this molecular crosstalk is necessary. We present here the characterization of a previously unreported MET RTK phosphosite, Serine 1016 (S1016) that represents a potential DDR-MET interface. MET S1016 phosphorylation increases in response to irradiation and is mainly targeted by DNA-dependent protein kinase (DNA-PK). Phosphoproteomics unveils an impact of the S1016A substitution on the overall long-term cell cycle regulation following DNA damage. Accordingly, the abrogation of this phosphosite strongly perturbs the phosphorylation of proteins involved in the cell cycle and formation of the mitotic spindle, enabling cells to bypass a G2 arrest upon irradiation and leading to the entry into mitosis despite compromised genome integrity. This results in the formation of abnormal mitotic spindles and a lower proliferation rate. Altogether, the current data uncover a novel signaling mechanism through which the DDR uses a growth factor receptor system for regulating and maintaining genome stability.
DNA 损伤反应（DDR）与致癌受体酪氨酸激酶（RTKs）下游的信号通路交织在一起。为了推动将靶向治疗作为放射增敏剂的应用研究，有必要更好地了解这种分子串扰。我们在这里介绍了一个以前未报道的 MET RTK 磷酸化位点丝氨酸 1016（S1016）的特征，它代表了一个潜在的 DDR-MET 界面。MET S1016 磷酸化会对辐照产生反应，主要由 DNA 依赖性蛋白激酶（DNA-PK）靶向。磷酸蛋白质组学揭示了 S1016A 取代对 DNA 损伤后细胞周期长期调控的整体影响。因此，该磷酸化位点的缺失会强烈干扰细胞周期和有丝分裂纺锤体形成过程中涉及的蛋白质的磷酸化，使细胞能够在照射后绕过 G2 期停滞，并在基因组完整性受损的情况下进入有丝分裂。这导致形成异常的有丝分裂纺锤体和较低的增殖率。总的来说，目前的数据揭示了一种新的信号机制，通过这种机制，DDR 利用生长因子受体系统来调节和维持基因组稳定性。
