The shieldin complex mediates 53BP1-dependent DNA repair.
Date
2018-08-02Author
Noordermeer, SM
Adam, S
Setiaputra, D
Barazas, M
Pettitt, SJ
Ling, AK
Olivieri, M
Álvarez-Quilón, A
Moatti, N
Zimmermann, M
Annunziato, S
Krastev, DB
Song, F
Brandsma, I
Frankum, J
Brough, R
Sherker, A
Landry, S
Szilard, RK
Munro, MM
McEwan, A
Goullet de Rugy, T
Lin, Z-Y
Hart, T
Moffat, J
Gingras, A-C
Martin, A
van Attikum, H
Jonkers, J
Lord, CJ
Rottenberg, S
Durocher, D
Type
Journal Article
Metadata
Show full item recordAbstract
53BP1 is a chromatin-binding protein that regulates the repair of DNA double-strand breaks by suppressing the nucleolytic resection of DNA termini1,2. This function of 53BP1 requires interactions with PTIP3 and RIF14-9, the latter of which recruits REV7 (also known as MAD2L2) to break sites10,11. How 53BP1-pathway proteins shield DNA ends is currently unknown, but there are two models that provide the best potential explanation of their action. In one model the 53BP1 complex strengthens the nucleosomal barrier to end-resection nucleases12,13, and in the other 53BP1 recruits effector proteins with end-protection activity. Here we identify a 53BP1 effector complex, shieldin, that includes C20orf196 (also known as SHLD1), FAM35A (SHLD2), CTC-534A2.2 (SHLD3) and REV7. Shieldin localizes to double-strand-break sites in a 53BP1- and RIF1-dependent manner, and its SHLD2 subunit binds to single-stranded DNA via OB-fold domains that are analogous to those of RPA1 and POT1. Loss of shieldin impairs non-homologous end-joining, leads to defective immunoglobulin class switching and causes hyper-resection. Mutations in genes that encode shieldin subunits also cause resistance to poly(ADP-ribose) polymerase inhibition in BRCA1-deficient cells and tumours, owing to restoration of homologous recombination. Finally, we show that binding of single-stranded DNA by SHLD2 is critical for shieldin function, consistent with a model in which shieldin protects DNA ends to mediate 53BP1-dependent DNA repair.
Collections
Subject
Cell Line
Animals
Humans
Mice
Multiprotein Complexes
Telomere-Binding Proteins
DNA, Single-Stranded
Immunoglobulin Class Switching
DNA Repair
Genes, BRCA1
Models, Biological
Female
Tumor Suppressor Protein p53
DNA Breaks, Double-Stranded
CRISPR-Cas Systems
Poly(ADP-ribose) Polymerase Inhibitors
Tumor Suppressor p53-Binding Protein 1
Research team
Gene Function
Language
eng
Date accepted
2018-05-15
License start date
2018-08
Citation
Nature, 2018, 560 (7716), pp. 117 - 121
Publisher
NATURE PUBLISHING GROUP