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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.

Original publication

DOI

10.1038/s41419-021-03437-w

Type

Journal article

Journal

Cell death & disease

Publication Date

02/2021

Volume

12

Addresses

MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK.

Keywords

Cell Line, Tumor, Humans, DNA Damage, Acid Anhydride Hydrolases, Cell Cycle Proteins, DNA-Binding Proteins, Nuclear Proteins, Cell Proliferation, DNA Repair, Substrate Specificity, Radiation Tolerance, Urinary Bladder Neoplasms, HEK293 Cells, Proteolysis, G2 Phase Cell Cycle Checkpoints, MRE11 Homologue Protein