PXD026912

PXD026912 is an original dataset announced via ProteomeXchange.

Title	MAD2L2 dimerization and TRIP13 control shieldin activity in DNA repair
Description	MAD2L2 (also known as REV7) functions in a diverse range of processes. It facilitates DNA lesion bypass through translesion synthesis (TLS), aids in interstrand crosslink repair and contributes to timely mitotic progression. Moreover, MAD2L2 plays an important role in DNA repair at DNA double strand breaks (DSBs) and uncapped telomeres. As the first identified member of the shieldin complex, consisting of MAD2L2, SHLD1, SHLD2 and SHLD3, it controls DNA repair pathway choice between non-homologous end-joining (NHEJ) and homologous recombination (HR) by counteracting DNA end-resection. Here we investigated the requirements for shieldin complex assembly and activity. Besides a dimerization surface, HORMA domain containing protein MAD2L2 has the extraordinary ability to wrap its C-terminal tail around an interacting peptide motif in SHLD3, thereby likely creating a very stable complex. We show that appropriate function of MAD2L2 in DNA repair as a member of the shieldin complex requires it to form a dimer that is mediated by SHLD2 and accelerates MAD2L2-SHLD3 interaction. Dimerization defective MAD2L2 impairs assembly of shieldin and fails to promote NHEJ at telomeres and during immunoglobulin class switch recombination (CSR). Moreover, dimerization of MAD2L2, along with the presence of SHLD3, allows the shieldin complex to interact with the AAA+ family ATPase TRIP13, known to drive topological switches in HORMA domain proteins. We find that appropriate levels of TRIP13 are important for proper shieldin (dis)assembly and activity in DNA repair. Together our data provide important insights in the dependencies for shieldin activity.
HostingRepository	PRIDE
AnnounceDate	2021-09-21
AnnouncementXML	Submission_2021-09-21_01:54:44.425.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Liesbeth Hoekman
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2021-06-24 08:22:38	ID requested
1	2021-09-21 01:35:55	announced
⏵ 2	2021-09-21 01:54:45	announced	2021-09-21: Updated project metadata.

10.1038/S41467-021-25724-Y;

de Krijger I, F, ö, hr B, P, é, rez SH, Vincendeau E, Serrat J, Thouin AM, Susvirkar V, Lescale C, Paniagua I, Hoekman L, Kaur S, Altelaar M, Deriano L, Faesen AC, Jacobs JJL, MAD2L2 dimerization and TRIP13 control shieldin activity in DNA repair. Nat Commun, 12(1):5421(2021) [pubmed]

submitter keyword: MAD2L2, TRIP13, DNA repair, shieldin, NHEJ

Maarten Altelaar
contact affiliation	Proteomics Facility, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands Biomolecular Mass Spectrometry and Proteomics, Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, Padualaan 8, 3584 CH Utrecht, The Netherlands
contact email	m.altelaar@nki.nl
lab head
Liesbeth Hoekman
contact affiliation	The Netherlands Cancer Institute, Amsterdam, The Netherlands.
contact email	l.hoekman@nki.nl
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2021/09/PXD026912

PRIDE project URI

• PRIDE
  1. PXD026912
     1. Label: PRIDE project
     2. Name: MAD2L2 dimerization and TRIP13 control shieldin activity in DNA repair