Compartmentalized DNA repair: Rif1 S-acylation links DNA double-strand break repair to the nuclear membrane

@article{Fontana2019CompartmentalizedDR,
  title={Compartmentalized DNA repair: Rif1 S-acylation links DNA double-strand break repair to the nuclear membrane},
  author={Gabriele A Fontana and Ulrich Rass},
  journal={Molecular \& Cellular Oncology},
  year={2019},
  volume={6}
}
ABSTRACT DNA double-strand breaks (DSBs) disrupt the structural integrity of chromosomes. Proper DSB repair pathway choice is critical to avoid the type of gross chromosomal rearrangements that characterize cancer cells. Recent findings reveal S-fatty acylation and membrane anchorage of Rap1-interacting factor 1 (Rif1) as a mechanism providing spatial control over DSB repair pathway choice. 
1 Citations
RIF1 Links Replication Timing with Fork Reactivation and DNA Double-Strand Break Repair
TLDR
High-resolution microscopic studies show that RIF1 cooperates with TP53BP1 to preserve 3D structure and epigenetic markers of genomic loci disrupted by DSBs, and further studies may reveal other aspects of common regulation of RT, DSBR, and fork reactivation by Rif1.

References

SHOWING 1-10 OF 10 REFERENCES
Nuclear compartmentalization of DNA repair.
Rif1 S-acylation mediates DNA double-strand break repair at the inner nuclear membrane
TLDR
Rif1 S-acylation facilitates the accumulation of Rif1 at DSBs, attenuation of DNA end-resection, and DSB repair by non-homologous end-joining by the DHHC family palmitoyl acyltransferase Pfa4.
Nuclear position dictates DNA repair pathway choice.
TLDR
It is demonstrated that DSBs induced at the nuclear membrane (but not at nuclear pores or nuclear interior) fail to rapidly activate the DNA damage response (DDR) and repair by homologous recombination (HR), revealing a new level of regulation in DSB repair controlled by spatial organization of DNA within the nucleus.
Shepherding DNA ends: Rif1 protects telomeres and chromosome breaks
TLDR
An overview of the actions of RIF1 at DNA ends is provided and how exclusion of end-processing factors might be the underlying principle allowing Rif1 to fulfill diverse biological roles at telomeres and chromosome breaks is explored.
Shieldin – the protector of DNA ends
TLDR
The identification of shieldin and the various models of Shieldin action are summarized and some outstanding questions requiring answers are highlighted to gain a full molecular understanding of shieldIn function.
DNA double-strand break repair-pathway choice in somatic mammalian cells
TLDR
This Review considers DSB repair-pathway choice in somatic mammalian cells as a series of ‘decision trees’, and explores how defective pathway choice can lead to genomic instability.
Rif1 maintains telomeres and mediates DNA repair by encasing DNA ends
TLDR
Crystal structures for the uncharacterized and conserved ∼125-kDa N-terminal domain of Rif1 from Saccharomyces cerevisiae (Rif1-NTD) are described, revealing an α-helical fold shaped like a shepherd's crook that fully encases DNA as a head-to-tail dimer in DNA repair.
Palmitoylation controls the dynamics of budding-yeast heterochromatin via the telomere-binding protein Rif1
TLDR
Genetic analyses indicated that PFA4 functioned upstream of RIF1, suggesting Rif1's roles at HM loci and telomeres were more complexly related than previously thought, and supported a model in which Pfa4-dependent palmitoylation of Rif 1 anchored it to the inner nuclear membrane, influencing its role in heterochromatin dynamics.
PARP inhibitors: Synthetic lethality in the clinic
TLDR
Current knowledge of PARP inhibitors and potential ways to maximize their clinical effectiveness are discussed, and interesting lessons for the development of other therapies are provided.
The physiology of protein S-acylation.
TLDR
This review introduces key features of S-acylation and tools to interrogate this process, and highlights the eclectic array of proteins regulated including membrane receptors, ion channels and transporters, enzymes and kinases, signaling adapters and chaperones, cell adhesion, and structural proteins.