TY - JOUR
T1 - The shieldin complex mediates 53BP1-dependent DNA repair
AU - Noordermeer, Sylvie M.
AU - Adam, Salomé
AU - Setiaputra, Dheva
AU - Barazas, Marco
AU - Pettitt, Stephen J.
AU - Ling, Alexanda K.
AU - Olivieri, Michele
AU - Álvarez-Quilón, Alejandro
AU - Moatti, Nathalie
AU - Zimmermann, Michal
AU - Annunziato, Stefano
AU - Krastev, Dragomir B.
AU - Song, Feifei
AU - Brandsma, Inger
AU - Frankum, Jessica
AU - Brough, Rachel
AU - Sherker, Alana
AU - Landry, Sébastien
AU - Szilard, Rachel K.
AU - Munro, Meagan M.
AU - McEwan, Andrea
AU - de Rugy, Théo Goullet
AU - Lin, Zhen Yuan
AU - Hart, Traver
AU - Moffat, Jason
AU - Gingras, Anne Claude
AU - Martin, Alberto
AU - van Attikum, Haico
AU - Jonkers, Jos
AU - Lord, Christopher J.
AU - Rottenberg, Sven
AU - Durocher, Daniel
N1 - Publisher Copyright:
© 2018 Springer Nature Limited. All rights reserved.
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
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U2 - 10.1038/s41586-018-0340-7
DO - 10.1038/s41586-018-0340-7
M3 - Article
C2 - 30022168
AN - SCOPUS:85050967099
SN - 0028-0836
VL - 560
SP - 117
EP - 121
JO - Nature
JF - Nature
IS - 7716
ER -