MRE11 UFMylation promotes ATM activation

• Published in: Nucleic acids research 2019-05, Vol.47 (8), p.4124-4135
• Main Authors: Wang, Zhifeng, Gong, Yamin, Peng, Bin, Shi, Ruifeng, Fan, Dan, Zhao, Hongchang, Zhu, Min, Zhang, Haoxing, Lou, Zhenkun, Zhou, Jianwei, Zhu, Wei-Guo, Cong, Yu-Sheng, Xu, Xingzhi
• Format: Article
• Language: English
• Subjects: A549 Cells; Acetylation; Acid Anhydride Hydrolases; Ataxia Telangiectasia Mutated Proteins - genetics; Ataxia Telangiectasia Mutated Proteins - metabolism; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Chromatin - metabolism; Chromatin - pathology; DNA Breaks, Double-Stranded; DNA Repair Enzymes - genetics; DNA Repair Enzymes - metabolism; DNA, Neoplasm - genetics; DNA, Neoplasm - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Gene Expression Regulation, Neoplastic; Genome Integrity, Repair and; HEK293 Cells; Humans; MRE11 Homologue Protein - antagonists & inhibitors; MRE11 Homologue Protein - genetics; MRE11 Homologue Protein - metabolism; Mutation; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Osteoblasts - metabolism; Osteoblasts - pathology; Phosphorylation; Protein Binding; Protein Processing, Post-Translational; Proteins - genetics; Proteins - metabolism; Recombinational DNA Repair; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Ubiquitination
• ISSN: 0305-1048; 1362-4962; 1362-4962
• DOI: 10.1093/nar/gkz110

Abstract A proper DNA damage response (DDR) is essential to maintain genome integrity and prevent tumorigenesis. DNA double-strand breaks (DSBs) are the most toxic DNA lesion and their repair is orchestrated by the ATM kinase. ATM is activated via the MRE11–RAD50–NBS1 (MRN) complex along with its autophosphorylation at S1981 and acetylation at K3106. Activated ATM rapidly phosphorylates a vast number of substrates in local chromatin, providing a scaffold for the assembly of higher-order complexes that can repair damaged DNA. While reversible ubiquitination has an important role in the DSB response, modification of the newly identified ubiquitin-like protein ubiquitin-fold modifier 1 and the function of UFMylation in the DDR is largely unknown. Here, we found that MRE11 is UFMylated on K282 and this UFMylation is required for the MRN complex formation under unperturbed conditions and DSB-induced optimal ATM activation, homologous recombination-mediated repair and genome integrity. A pathogenic mutation MRE11(G285C) identified in uterine endometrioid carcinoma exhibited a similar cellular phenotype as the UFMylation-defective mutant MRE11(K282R). Taken together, MRE11 UFMylation promotes ATM activation, DSB repair and genome stability, and potentially serves as a therapeutic target.