SPRTN protease-cleaved MRE11 decreases DNA repair and radiosensitises cancer cells
| Autor: | Anne E. Kiltie, Chee Kin Then, Sophie Ellermann, J.A. Newman, Junetha Syed, Ignacio Torrecilla, Iolanda Vendrell, Kristijan Ramadan, Juri Na, Roman Fischer |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
MRE11 Homologue Protein/genetics DNA Repair Cell Cycle Proteins Radiation Tolerance Substrate Specificity Endonuclease chemistry.chemical_compound 0302 clinical medicine 0303 health sciences MRE11 Homologue Protein Tumor biology lcsh:Cytology Chemistry DNA damage and repair Nuclear Proteins Cell biology Acid Anhydride Hydrolases DNA-Binding Proteins G2 Phase Cell Cycle Checkpoints Urogenital diseases G2 Phase Cell Cycle Checkpoints/radiation effects 030220 oncology & carcinogenesis Exonuclease DNA damage DNA repair Immunology Urinary Bladder Neoplasms/enzymology Cell Proliferation/radiation effects Article Cell Line 03 medical and health sciences Cellular and Molecular Neuroscience Cell Line Tumor Humans lcsh:QH573-671 030304 developmental biology Cell Proliferation Cell Cycle Proteins/genetics Mutagenesis Cell Biology Acid Anhydride Hydrolases/genetics Nuclear Proteins/genetics enzymes and coenzymes (carbohydrates) HEK293 Cells MRN complex Urinary Bladder Neoplasms Rad50 Proteolysis biology.protein DNA DNA-Binding Proteins/genetics DNA Damage |
| Zdroj: | Cell Death & Disease Cell death & disease, 12(2). Nature Publishing Group Cell Death and Disease, Vol 12, Iss 2, Pp 1-17 (2021) |
| ISSN: | 2041-4889 |
| DOI: | 10.1038/s41419-021-03437-w |
| Popis: | The human MRE11/RAD50/NBS1 (MRN) complex plays a crucial role in sensing and repairing DNA DSB. MRE11 possesses dual 3′−5′ exonuclease and endonuclease activity and forms the core of the multifunctional MRN complex. We previously identified a C-terminally truncated form of MRE11 (TR-MRE11) associated with post-translational MRE11 degradation. Here we identified SPRTN as the essential protease for the formation of TR-MRE11 and characterised the role of this MRE11 form in its DNA damage response (DDR). Using tandem mass spectrometry and site-directed mutagenesis, the SPRTN-dependent cleavage site for MRE11 was identified between 559 and 580 amino acids. Despite the intact interaction of TR-MRE11 with its constitutive core complex proteins RAD50 and NBS1, both nuclease activities of truncated MRE11 were dramatically reduced due to its deficient binding to DNA. Furthermore, lack of the MRE11 C-terminal decreased HR repair efficiency, very likely due to abolished recruitment of TR-MRE11 to the sites of DNA damage, which consequently led to increased cellular radiosensitivity. The presence of this DNA repair-defective TR-MRE11 could explain our previous finding that the high MRE11 protein expression by immunohistochemistry correlates with improved survival following radical radiotherapy in bladder cancer patients. |
| Databáze: | OpenAIRE |
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