FEATURED PUBLICATIONS


Sifri2023

An AlphaFold2 map of the 53BP1 pathway identifies a direct SHLD3–RIF1 interaction critical for shieldin activity
Chérine Sifri, Lisa Hoeg, Daniel Durocher, Dheva Setiaputra
EMBO Reports (2023)


In this study, we used AlphaFold-Multimer to exhaustively predict pairwise interactions within the 53BP1-RIF1-shieldin-CST pathway. We were remarkably successful in identifying the structural basis of multiple known interactions, while also discovering new interfaces. In particular, this analysis yielded the novel interface between RIF1 and SHLD3 which we confirm to occur both in vitro and in cells, and that disrupting this interaction is detrimental to shieldin's DNA repair function.
Setiaputra2023

RIF1 acts in DNA repair through phosphopeptide recognition of 53BP1
Dheva Setiaputra, Cristina Escribano-Diaz, Julia Reinert, Pooja Sadana, Dali Zong, Elsa Callen, Chérine Sifri, Jan Seebacher, André Nussenzweig, Nicolas Thoma, Daniel Durocher
Molecular Cell (2022)


RIF1 is known to be recruited to DNA double-strand breaks through interactions with the ATM-phosphorylated 53BP1 N-terminus. However, which of 53BP1's 28 phosphorylation sites are important was unknown. Here we discovered that three separate 53BP1 di-phosphorylated motifs are essential for RIF1 recruitment to breaks, and that disrupting these interactions—along with phosphoresidues important for shieldin recruitment—are essential for 53BP1-mediated DNA repair.
Noordermeer2018

The shieldin complex mediates 53BP1-dependent DNA repair
Sylvie Noordermeer, Salomé Adam, Dheva Setiaputra, Marco Barazas, Stephen Pettitt, Alexanda Ling, Michele Olivieri, Alejandro Álvarez-Quilón, Nathalie Moatti, Michal Zimmermann, Stefano Annunziato, Dragomir Krastev, Feifei Song, Inger Brandsma, Jessica Frankum, Rachel Brough, Alana Sherker, Sébastien Landry, Rachel Szilard, Meagan Munro, Andrea McEwan, Théo Goullet de Rugy, Zhen-Yuan Lin, Traver Hart, Jason Moffat, Anne-Claude Gingras, Alberto Martin, Haico van Attikum, Jos Jonkers, Christopher Lord, Sven Rottenberg & Daniel Durocher
Nature (2018)


PARP inhibitors are a class of chemotherapeutic that are exquisitely toxic to BRCA1 mutated tumors do to their inability to repair DNA lesions using homologous recombination (HR). Loss of the DNA repair factor 53BP1 rescues this sensitivity by restoring HR. The molecular basis of 53BP1 function was unclear. Using CRISPR genome-wide screens, we discovered the shieldin complex as being a downstream effector of 53BP1 that mediates its suppression of HR. Furthermore, we determined that the single-stranded DNA binding activity of this complex is essential for its role in DNA repair.

SELECTED PUBLICATIONS

2023
An AlphaFold2 map of the 53BP1 pathway identifies a direct SHLD3–RIF1 interaction critical for shieldin activity. Sifri C, Hoeg L, Durocher D, Setiaputra D. EMBO Reports. doi:10.15252/embr.202356834.

2022
RIF1 acts in DNA repair through phosphopeptide recognition of 53BP1. Setiaputra D, Escribano-Diaz C, Reinert JK, Sadana P, Zong D, Callen E, Sifri C, Seebacher J, Nussenzweig A, Thomä NH, Durocher D. Molecular Cell. doi:10.1016/j.molcel.2022.01.025.

2021
The CIP2A–TOPBP1 axis safeguards chromosome stability and is a synthetic lethal target for BRCA-mutated cancer. Adam S, Rossi SE, Moatti N, Zompit MDM, Xue Y, Ng TF, Álvarez-Quilón A, Desjardins J, Bhaskaran V, Martino G, Setiaputra D, Noordermeer SM, Ohsumi TK, Hustedt N, Szilard RK, Chaudhary N, Munro M, Veloso A, Melo H, Yin SY, Papp R, Young JTF, Zinda M, Stucki M, Durocher D. Nature Cancer. doi:10.1038/s43018-021-00266-w.

2020
Endogenous DNA 3′ blocks are vulnerabilities for BRCA1 and BRCA2 deficiency and are reversed by the APE2 nuclease. Álvarez-Quilón A, Wojtaszek JL, Mathieu MC, Patel T, Appel CD, Hustedt N, Rossi SE, Wallace BD, Setiaputra D, Adam S, Ohashi Y, Melo H, Cho T, Gervais C, Muñoz IM, Grazzini E, Young JTF, Rouse J, Zinda M, Williams RS, Durocher D. Molecular Cell. doi:10.1016/j.molcel.2020.05.021.

2019
Shieldin—the protector of DNA ends. Setiaputra D, Durocher D. EMBO Reports. doi:10.15252/embr.201847560.

Control of homologous recombination by the HROB–MCM8–MCM9 pathway. Hustedt N, Saito Y, Zimmermann M, Álvarez-Quilón A, Setiaputra D, Adam S, McEwan A, Yuan JY, Olivieri M, Zhao Y, Kanemaki MT, Jurisicova A, Durocher D. Genes and Development. doi:10.1101/gad.329508.119.

2018
The shieldin complex mediates 53BP1-dependent DNA repair. Noordermeer SM, Adam A*, 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 ZY, Hart T, Moffat J, Gingras AC, Martin A, van Attikum H, Jonkers J, Lord CJ, Rottenberg S, Durocher D. Nature. doi:10.1038/s41586-018-0340-7. *Co-first authors.