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Nat Commun. 2019 Jun 10;10(1):2535. doi: 10.1038/s41467-019-10349-z.

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

Author information

1
Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058, Basel, Switzerland.
2
Department of Health Sciences and Technology, ETH Zürich, Schmelzbergstrasse 9, CH-8092, Zürich, Switzerland.
3
Faculty of Natural Sciences, University of Basel, Petersplatz 10, CH-4003, Basel, Switzerland.
4
Department of Molecular Biology and Institute of Genetics and Genomics in Geneva (iGE3), University of Geneva, 30 Quai Ernest-Ansermet, CH-1211, Geneva, Switzerland.
5
Institut de Biologie Physico-Chimique, UMR8226, Laboratoire de Biologie Moléculaire et Cellulaire des Eucaryotes, Sorbonne Université, CNRS/UPMC, 13 rue Pierre et Marie Curie, 75005, Paris, France.
6
Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058, Basel, Switzerland. U.W.Rass@sussex.ac.uk.
7
Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, BN1 9RQ, UK. U.W.Rass@sussex.ac.uk.

Abstract

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.

PMID:
31182712
PMCID:
PMC6557901
DOI:
10.1038/s41467-019-10349-z
[Indexed for MEDLINE]
Free PMC Article

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