Human RIF1-Protein Phosphatase 1 Prevents Degradation and Breakage of Nascent DNA on Replication Stalling

Javier Garzón; Sebastian Ursich; Massimo Lopes; Shin-ichiro Hiraga; Anne D. Donaldson

doi:10.1016/j.celrep.2019.05.002

Human RIF1-Protein Phosphatase 1 Prevents Degradation and Breakage of Nascent DNA on Replication Stalling

Javier Garzón, Sebastian Ursich, Massimo Lopes, Shin-ichiro Hiraga, Anne D. Donaldson (Corresponding Author)

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Abstract

RIF1 is a multifunctional protein implicated in controlling DNA replication and repair. Here we show that human RIF1 protects nascent DNA from over-degradation at stalled replication forks. The major nuclease resecting nascent DNA in the absence of RIF1 is DNA2, operating with WRN as an accessory helicase. We show that RIF1 acts with Protein Phosphatase 1 to prevent over-degradation, and that RIF1 limits phosphorylation of WRN at sites implicated in resection control. Protection by RIF1 against inappropriate degradation prevents accumulation of DNA breakage. Our observations uncover a crucial function of human RIF1 in preventing genome instability by protecting forks from unscheduled DNA2-WRN-mediated degradation.

Original language	English
Pages (from-to)	2558-2566.e4
Number of pages	14
Journal	Cell Reports
Volume	27
Issue number	9
Early online date	28 May 2019
DOIs	https://doi.org/10.1016/j.celrep.2019.05.002
Publication status	Published - 28 May 2019

Keywords

DNA Replication
Fork Protection
Replication stress
Genome Integrity
RIF1-PP1
DNA2
WRN

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2019.05.002Licence: CC BY

Human RIF1-Protein Phosphatase 1 Prevents Degradation and Breakage of Nascent DNA on Replication Stalling
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Final published version, 2.37 MBLicence: CC BY

Cite this

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title = "Human RIF1-Protein Phosphatase 1 Prevents Degradation and Breakage of Nascent DNA on Replication Stalling",

abstract = "RIF1 is a multifunctional protein implicated in controlling DNA replication and repair. Here we show that human RIF1 protects nascent DNA from over-degradation at stalled replication forks. The major nuclease resecting nascent DNA in the absence of RIF1 is DNA2, operating with WRN as an accessory helicase. We show that RIF1 acts with Protein Phosphatase 1 to prevent over-degradation, and that RIF1 limits phosphorylation of WRN at sites implicated in resection control. Protection by RIF1 against inappropriate degradation prevents accumulation of DNA breakage. Our observations uncover a crucial function of human RIF1 in preventing genome instability by protecting forks from unscheduled DNA2-WRN-mediated degradation. ",

keywords = "DNA Replication, Fork Protection, Replication stress, Genome Integrity, RIF1-PP1, DNA2, WRN",

author = "Javier Garz{\'o}n and Sebastian Ursich and Massimo Lopes and Shin-ichiro Hiraga and Donaldson, {Anne D.}",

note = "We thank the Microscopy Core and Proteomics Core Facilities at Aberdeen University for assistance and analysis. pCMV-Flag-WRN plasmid was kindly gifted by Pietro Pichierri. NSC-105808 from Grzegorz Ira lab was gifted by Alessandro Vindigni. We thank all the members of our lab and Takashi Kubota for helpful discussions. This research was supported by Cancer Research UK Programme Award A19059 to ADD and SH. ",

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AU - Garzón, Javier

AU - Ursich, Sebastian

AU - Lopes, Massimo

AU - Hiraga, Shin-ichiro

AU - Donaldson, Anne D.

N1 - We thank the Microscopy Core and Proteomics Core Facilities at Aberdeen University for assistance and analysis. pCMV-Flag-WRN plasmid was kindly gifted by Pietro Pichierri. NSC-105808 from Grzegorz Ira lab was gifted by Alessandro Vindigni. We thank all the members of our lab and Takashi Kubota for helpful discussions. This research was supported by Cancer Research UK Programme Award A19059 to ADD and SH.

PY - 2019/5/28

Y1 - 2019/5/28

N2 - RIF1 is a multifunctional protein implicated in controlling DNA replication and repair. Here we show that human RIF1 protects nascent DNA from over-degradation at stalled replication forks. The major nuclease resecting nascent DNA in the absence of RIF1 is DNA2, operating with WRN as an accessory helicase. We show that RIF1 acts with Protein Phosphatase 1 to prevent over-degradation, and that RIF1 limits phosphorylation of WRN at sites implicated in resection control. Protection by RIF1 against inappropriate degradation prevents accumulation of DNA breakage. Our observations uncover a crucial function of human RIF1 in preventing genome instability by protecting forks from unscheduled DNA2-WRN-mediated degradation.

AB - RIF1 is a multifunctional protein implicated in controlling DNA replication and repair. Here we show that human RIF1 protects nascent DNA from over-degradation at stalled replication forks. The major nuclease resecting nascent DNA in the absence of RIF1 is DNA2, operating with WRN as an accessory helicase. We show that RIF1 acts with Protein Phosphatase 1 to prevent over-degradation, and that RIF1 limits phosphorylation of WRN at sites implicated in resection control. Protection by RIF1 against inappropriate degradation prevents accumulation of DNA breakage. Our observations uncover a crucial function of human RIF1 in preventing genome instability by protecting forks from unscheduled DNA2-WRN-mediated degradation.

KW - DNA Replication

KW - Fork Protection

KW - Replication stress

KW - Genome Integrity

KW - RIF1-PP1

KW - DNA2

KW - WRN

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JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

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ER -

Human RIF1-Protein Phosphatase 1 Prevents Degradation and Breakage of Nascent DNA on Replication Stalling

Abstract

Keywords

UN SDGs

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Shinichiro Hiraga

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Human RIF1-Protein Phosphatase 1 Prevents Degradation and Breakage of Nascent DNA on Replication Stalling

Abstract

Keywords

UN SDGs

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Shinichiro Hiraga

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