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SPRTN protease-cleaved MRE11 decreases DNA repair and radiosensitises cancer cells
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) associate...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870818/ https://www.ncbi.nlm.nih.gov/pubmed/33558481 http://dx.doi.org/10.1038/s41419-021-03437-w |
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author | Na, Juri Newman, Joseph A. Then, Chee Kin Syed, Junetha Vendrell, Iolanda Torrecilla, Ignacio Ellermann, Sophie Ramadan, Kristijan Fischer, Roman Kiltie, Anne E. |
author_facet | Na, Juri Newman, Joseph A. Then, Chee Kin Syed, Junetha Vendrell, Iolanda Torrecilla, Ignacio Ellermann, Sophie Ramadan, Kristijan Fischer, Roman Kiltie, Anne E. |
author_sort | Na, Juri |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7870818 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-78708182021-02-11 SPRTN protease-cleaved MRE11 decreases DNA repair and radiosensitises cancer cells Na, Juri Newman, Joseph A. Then, Chee Kin Syed, Junetha Vendrell, Iolanda Torrecilla, Ignacio Ellermann, Sophie Ramadan, Kristijan Fischer, Roman Kiltie, Anne E. Cell Death Dis Article 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. Nature Publishing Group UK 2021-02-08 /pmc/articles/PMC7870818/ /pubmed/33558481 http://dx.doi.org/10.1038/s41419-021-03437-w Text en © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Na, Juri Newman, Joseph A. Then, Chee Kin Syed, Junetha Vendrell, Iolanda Torrecilla, Ignacio Ellermann, Sophie Ramadan, Kristijan Fischer, Roman Kiltie, Anne E. SPRTN protease-cleaved MRE11 decreases DNA repair and radiosensitises cancer cells |
title | SPRTN protease-cleaved MRE11 decreases DNA repair and radiosensitises cancer cells |
title_full | SPRTN protease-cleaved MRE11 decreases DNA repair and radiosensitises cancer cells |
title_fullStr | SPRTN protease-cleaved MRE11 decreases DNA repair and radiosensitises cancer cells |
title_full_unstemmed | SPRTN protease-cleaved MRE11 decreases DNA repair and radiosensitises cancer cells |
title_short | SPRTN protease-cleaved MRE11 decreases DNA repair and radiosensitises cancer cells |
title_sort | sprtn protease-cleaved mre11 decreases dna repair and radiosensitises cancer cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870818/ https://www.ncbi.nlm.nih.gov/pubmed/33558481 http://dx.doi.org/10.1038/s41419-021-03437-w |
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