MAD2L2 dimerization and TRIP13 control shieldin activity in DNA repair.
ATPases Associated with Diverse Cellular Activities
/ chemistry
Animals
Binding Sites
Cell Cycle Proteins
/ chemistry
Cell Line
Cell Line, Tumor
Cisplatin
/ pharmacology
DNA
/ chemistry
DNA Breaks, Double-Stranded
DNA Repair
DNA-Binding Proteins
/ chemistry
Fibroblasts
/ cytology
Gene Expression
HEK293 Cells
HeLa Cells
Humans
Mad2 Proteins
/ chemistry
Mice
Phthalazines
/ pharmacology
Piperazines
/ pharmacology
Protein Binding
Protein Interaction Domains and Motifs
Protein Multimerization
Recombinant Proteins
/ chemistry
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
14 09 2021
14 09 2021
Historique:
received:
04
02
2021
accepted:
28
08
2021
entrez:
15
9
2021
pubmed:
16
9
2021
medline:
13
10
2021
Statut:
epublish
Résumé
MAD2L2 (REV7) plays an important role in DNA double-strand break repair. As a member of the shieldin complex, consisting of MAD2L2, SHLD1, SHLD2 and SHLD3, it controls DNA repair pathway choice by counteracting DNA end-resection. Here we investigated the requirements for shieldin complex assembly and activity. Besides a dimerization-surface, HORMA-domain protein MAD2L2 has the extraordinary ability to wrap its C-terminus around SHLD3, likely creating a very stable complex. We show that appropriate function of MAD2L2 within shieldin requires its dimerization, mediated by SHLD2 and accelerating MAD2L2-SHLD3 interaction. Dimerization-defective MAD2L2 impairs shieldin assembly and fails to promote NHEJ. Moreover, MAD2L2 dimerization, along with the presence of SHLD3, allows shieldin to interact with the TRIP13 ATPase, 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.
Identifiants
pubmed: 34521823
doi: 10.1038/s41467-021-25724-y
pii: 10.1038/s41467-021-25724-y
pmc: PMC8440562
doi:
Substances chimiques
Cell Cycle Proteins
0
DNA-Binding Proteins
0
MAD2L2 protein, human
0
Mad2 Proteins
0
Phthalazines
0
Piperazines
0
Recombinant Proteins
0
SHLD1 protein, human
0
SHLD2 protein, human
0
SHLD3 protein, human
0
DNA
9007-49-2
ATPases Associated with Diverse Cellular Activities
EC 3.6.4.-
TRIP13 protein, human
EC 3.6.4.-
Cisplatin
Q20Q21Q62J
olaparib
WOH1JD9AR8
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5421Informations de copyright
© 2021. The Author(s).
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