PXD017964

PXD017964 is an original dataset announced via ProteomeXchange.

Title	A truncated MRE11 form induced by SPRTN is deficient in DNA repair and radiosensitises cancer cells
Description	he human MRE11/RAD50/NBS1 (MRN) complex plays a crucial role in sensing and repairing DNA DSB. MRE11 possesses 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 the approximate cleavage site of TR-MRE11 at 559-580 amino acids, its DNA damage repair function and the factors regulating TR-MRE11 accumulation. The nuclease enzymatic activity of TR-MRE11 was dramatically reduced, associated with a lack of DNA binding efficiency, whilst TR-MRE11 still interacted efficiently with RAD50 and NBS1. Lack of the MRE11 C-terminal resulted in deficient HR repair and increased cellular radiosensitivity. Knockdown of SprT-like N-terminal domain (SPRTN), an essential metalloprotease for DNA-protein crosslink repair, resulted in failure of MRE11 cleavage, with TR-MRE11 protein levels being positively correlated with SPRTN protein expression. The presence of this DNA repair-defective C-terminal truncation could explain the finding of high MRE11 expression, by immunohistochemistry using an antibody against MRE11 prior to the C-terminal, being associated with survival following radical radiotherapy in cancer patients. Ultimately, understanding the functional differences between intact and repair-defective MRE11 may lead to improvements in patient outcomes through a more informed choice of treatment.
HostingRepository	PRIDE
AnnounceDate	2021-02-24
AnnouncementXML	Submission_2021-02-23_22:30:25.649.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD017964
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	iolanda Vendrell
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	Deamidated; Oxidation; Acetyl; Carbamidomethyl
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2020-03-10 02:36:36	ID requested
1	2021-02-23 07:22:38	announced
⏵ 2	2021-02-23 22:30:26	announced	2021-02-24: Updated project metadata.

Na J, Newman JA, Then CK, Syed J, Vendrell I, Torrecilla I, Ellermann S, Ramadan K, Fischer R, Kiltie AE, SPRTN protease-cleaved MRE11 decreases DNA repair and radiosensitises cancer cells. Cell Death Dis, 12(2):165(2021) [pubmed]

10.1038/S41419-021-03437-W;

submitter keyword: MRE11, C-terminal truncation, MRE11 cleavage, SPRTN, DNA repair

Professor Anne Kiltie
contact affiliation	CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK
contact email	anne.kiltie@oncology.ox.ac.uk
lab head
iolanda Vendrell
contact affiliation	CRUK-MRC Oxford Institute for Radiation Oncology, Oxford University
contact email	iolanda.vendrell@ndm.ox.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD017964
     1. Label: PRIDE project
     2. Name: A truncated MRE11 form induced by SPRTN is deficient in DNA repair and radiosensitises cancer cells