Pan-cancer antagonistic inhibition pattern of ATM-driven G2/M checkpoint pathway vs other DNA repair pathways

• Published in: DNA repair Vol. 123; p. 103448
• Main Authors: Zolotovskaia, Marianna A., Modestov, Alexander A., Suntsova, Maria V., Rachkova, Anastasia A., Koroleva, Elena V., Poddubskaya, Elena V., Sekacheva, Marina I., Tkachev, Victor S., Garazha, Andrew V., Glusker, Alexander A., Seryakov, Aleksander P., Vladimirova, Uliana S., Rumiantsev, Pavel O., Moisseev, Aleksey A., Zharkov, Dmitry O., Kuzmin, Denis V., Zhao, Xiaowen, Prassolov, Vladimir S., Shegay, Petr V., Li, Xinmin, Steinbichler, Teresa B., Kim, Ella, Sorokin, Maxim I., Wang, Ye, Buzdin, Anton A.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-03-2023
• Subjects: Apoptosis; Ataxia Telangiectasia Mutated Proteins - metabolism; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Checkpoint Kinase 1 - metabolism; DNA Damage; DNA Repair; G2 Phase Cell Cycle Checkpoints - genetics; G2/M arrest pathway; Humans; Molecular pathway analysis; Neoplasms - genetics; Oncobox clinical investigation; Proteomic profiling; Proteomics; RNA sequencing; Systems biology; Tumor Suppressor Protein p53 - metabolism; RNA sequencing; G2/M arrest pathway; Oncobox clinical investigation; Molecular pathway analysis; Proteomic profiling; Systems biology
• DOI: 10.1016/j.dnarep.2023.103448
• EISSN: 1568-7856
• ISSN: 1568-7864

DNA repair mechanisms keep genome integrity and limit tumor-associated alterations and heterogeneity, but on the other hand they promote tumor survival after radiation and genotoxic chemotherapies. We screened pathway activation levels of 38 DNA repair pathways in nine human cancer types (gliomas, breast, colorectal, lung, thyroid, cervical, kidney, gastric, and pancreatic cancers). We took RNAseq profiles of the experimental 51 normal and 408 tumor samples, and from The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium databases - of 500/407 normal and 5752/646 tumor samples, and also 573 normal and 984 tumor proteomic profiles from Proteomic Data Commons portal. For all the samplings we observed a congruent trend that all cancer types showed inhibition of G2/M arrest checkpoint pathway compared to the normal samples, and relatively low activities of p53-mediated pathways. In contrast, other DNA repair pathways were upregulated in most of the cancer types. The G2/M checkpoint pathway was statistically significantly downregulated compared to the other DNA repair pathways, and this inhibition was strongly impacted by antagonistic regulation of (i) promitotic genes CCNB and CDK1, and (ii) GADD45 genes promoting G2/M arrest. At the DNA level, we found that ATM, TP53, and CDKN1A genes accumulated loss of function mutations, and cyclin B complex genes – transforming mutations. These findings suggest importance of activation for most of DNA repair pathways in cancer progression, with remarkable exceptions of G2/M checkpoint and p53-related pathways which are downregulated and neutrally activated, respectively.
•Most of DNA repair pathways are upregulated in cancers.•In contrast, G2/M checkpoint pathway is instead strongly inhibited.•Whereas other p53-related pathways are neutrally activated.•G2/M checkpoint inhibition is mediated by CCNB, CDK1, GADD45 expression.•ATM, TP53, CDKN1A accumulate loss of function, CCNB – transforming mutations.