The shieldin complex mediates 53BP1-dependent DNA repair

Sylvie M. Noordermeer, Salomé Adam, Dheva Setiaputra, Marco Barazas, Stephen J. Pettitt, Alexanda K. Ling, Michele Olivieri, Alejandro Álvarez-Quilón, Nathalie Moatti, Michal Zimmermann, Stefano Annunziato, Dragomir B. Krastev, Feifei Song, Inger Brandsma, Jessica Frankum, Rachel Brough, Alana Sherker, Sébastien Landry, Rachel K. Szilard, Meagan M. Munro, Andrea McEwan, Théo Goullet de Rugy, Zhen-Yuan Lin, Traver Hart, Jason Moffat, Anne-Claude Gingras, Alberto Martin, Haico Attikum, Jos Jonkers, Christopher J. Lord, Sven Rottenberg and Daniel Durocher ()
Additional contact information
Sylvie M. Noordermeer: Mount Sinai Hospital, Toronto
Salomé Adam: Mount Sinai Hospital, Toronto
Dheva Setiaputra: Mount Sinai Hospital, Toronto
Marco Barazas: Oncode Institute, Netherlands Cancer Institute
Stephen J. Pettitt: The Institute of Cancer Research
Alexanda K. Ling: University of Toronto, Toronto
Michele Olivieri: Mount Sinai Hospital, Toronto
Alejandro Álvarez-Quilón: Mount Sinai Hospital, Toronto
Nathalie Moatti: Mount Sinai Hospital, Toronto
Michal Zimmermann: Mount Sinai Hospital, Toronto
Stefano Annunziato: Oncode Institute, Netherlands Cancer Institute
Dragomir B. Krastev: The Institute of Cancer Research
Feifei Song: The Institute of Cancer Research
Inger Brandsma: The Institute of Cancer Research
Jessica Frankum: The Institute of Cancer Research
Rachel Brough: The Institute of Cancer Research
Alana Sherker: Mount Sinai Hospital, Toronto
Sébastien Landry: Mount Sinai Hospital, Toronto
Rachel K. Szilard: Mount Sinai Hospital, Toronto
Meagan M. Munro: Mount Sinai Hospital, Toronto
Andrea McEwan: Mount Sinai Hospital, Toronto
Théo Goullet de Rugy: Mount Sinai Hospital, Toronto
Zhen-Yuan Lin: Mount Sinai Hospital, Toronto
Traver Hart: University of Texas MD Anderson Cancer Center
Jason Moffat: University of Toronto, Toronto
Anne-Claude Gingras: Mount Sinai Hospital, Toronto
Alberto Martin: University of Toronto, Toronto
Haico Attikum: Leiden University Medical Center
Jos Jonkers: Oncode Institute, Netherlands Cancer Institute
Christopher J. Lord: The Institute of Cancer Research
Sven Rottenberg: Oncode Institute, Netherlands Cancer Institute
Daniel Durocher: Mount Sinai Hospital, Toronto

Nature, 2018, vol. 560, issue 7716, 117-121

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41586-018-0340-7

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