Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058, Basel, Switzerland.
Department of Health Sciences and Technology, ETH Zürich, Schmelzbergstrasse 9, CH-8092, Zürich, Switzerland.
Nat Commun. 2019 Jun 10;10(1):2535. 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.
Rif1 参与端粒稳态、DNA 复制定时以及从酵母到人 DNA 双链断裂 (DSB) 修复途径的选择。使 Rif1 能够发挥其多种作用的分子机制仍有待确定。在这里，我们证明 Rif1 在其保守的 N 端结构域内的半胱氨酸残基 C466 和 C473 处被 DHHC 家族棕榈酰转移酶 Pfa4 酰化。 Rif1 的 S 酰化促进了 Rif1 在 DSB 处的积累，减弱了 DNA 末端切除，并通过非同源末端连接 (NHEJ) 修复 DSB。这些发现确定 S 酰化是一种调节 DNA 修复的翻译后修饰。S 酰化的 Rif1 在核内膜附近组装局部的 DNA 损伤反应，揭示了通过将脂肪酸酰化的修复因子隔离在内核膜上来选择隔室化 DSB 修复途径的机制。
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