Rif1 S-acylation mediates DNA double-strand break repair at the inner nuclear membrane

• Published in: Nature communications Vol. 10; no. 1; p. 2535
• Main Authors: Fontana, Gabriele A, Hess, Daniel, Reinert, Julia K, Mattarocci, Stefano, Falquet, Benoît, Klein, Dominique, Shore, David, Thomä, Nicolas H, Rass, Ulrich
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 10.06.2019; Nature Publishing Group UK; Nature Portfolio
• Subjects: Acylation; Acyltransferase; Attenuation; Biochemistry, Molecular Biology; Damage localization; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA Breaks, Double-Stranded; DNA damage; DNA End-Joining Repair; DNA Repair; Double-strand break repair; Homeostasis; Homology; Life Sciences; Molecular modelling; Non-homologous end joining; Nuclear Envelope - metabolism; Repair; Repressor Proteins - genetics; Repressor Proteins - metabolism; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Telomere-Binding Proteins - genetics; Telomere-Binding Proteins - metabolism; Yeast; Nuclear envelope; Post-translational modifications; Non-homologous-end joining
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-10349-z

Rif1 is involved in telomere homeostasis, DNA replication timing, and DNA double-strand break (DSB) repair pathway choice from yeast to human. The molecular mechanisms that enable Rif1 to fulfill its diverse roles remain to be determined. Here, we demonstrate that Rif1 is S-acylated within its conserved N-terminal domain at cysteine residues C466 and C473 by the DHHC family palmitoyl acyltransferase Pfa4. Rif1 S-acylation facilitates the accumulation of Rif1 at DSBs, the attenuation of DNA end-resection, and DSB repair by non-homologous end-joining (NHEJ). These findings identify S-acylation as a posttranslational modification regulating DNA repair. S-acylated Rif1 mounts a localized DNA-damage response proximal to the inner nuclear membrane, revealing a mechanism of compartmentalized DSB repair pathway choice by sequestration of a fatty acylated repair factor at the inner nuclear membrane.