ATM-dependent downregulation of USP7/HAUSP by PPM1G activates p53 response to DNA damage

Svetlana V Khoronenkova; Irina I Dianova; Nicola Ternette; Benedikt M Kessler; Jason L Parsons; Grigory L Dianov

doi:10.1016/j.molcel.2012.01.021

ATM-dependent downregulation of USP7/HAUSP by PPM1G activates p53 response to DNA damage

Svetlana V Khoronenkova, Irina I Dianova, Nicola Ternette, Benedikt M Kessler, Jason L Parsons, Grigory L Dianov

Cancer and Genomic Sciences

Research output: Contribution to journal › Article › peer-review

Abstract

The deubiquitylation enzyme USP7/HAUSP plays a major role in regulating genome stability and cancer prevention by controlling the key proteins involved in the DNA damage response. Despite this important role in controlling other proteins, USP7 itself has not been recognized as a target for regulation. Here, we report that USP7 regulation plays a central role in DNA damage signal transmission. We find that stabilization of Mdm2, and correspondingly p53 downregulation in unstressed cells, is accomplished by a specific isoform of USP7 (USP7S), which is phosphorylated at serine 18 by the protein kinase CK2. Phosphorylation stabilizes USP7S and thus contributes to Mdm2 stabilization and downregulation of p53. After ionizing radiation, dephosphorylation of USP7S by the ATM-dependent protein phosphatase PPM1G leads to USP7S downregulation, followed by Mdm2 downregulation and accumulation of p53. Our findings provide a quantitative transmission mechanism of the DNA damage signal to coordinate a p53-dependent DNA damage response.

Original language	English
Pages (from-to)	801-13
Number of pages	13
Journal	Molecular Cell
Volume	45
Issue number	6
DOIs	https://doi.org/10.1016/j.molcel.2012.01.021
Publication status	Published - 30 Mar 2012

Bibliographical note

Keywords

Amino Acid Sequence
Ataxia Telangiectasia Mutated Proteins
Casein Kinase II/genetics
Cell Cycle Checkpoints
Cell Cycle Proteins/genetics
DNA Damage/physiology
DNA-Binding Proteins/genetics
Down-Regulation
HeLa Cells/radiation effects
Humans
Molecular Sequence Data
Phosphoprotein Phosphatases/genetics
Phosphorylation
Protein Phosphatase 2C
Protein Serine-Threonine Kinases/genetics
Proto-Oncogene Proteins c-mdm2/genetics
Radiation, Ionizing
Serine/metabolism
Signal Transduction
Tumor Suppressor Protein p53/genetics
Tumor Suppressor Proteins/genetics
Ubiquitin Thiolesterase/genetics
Ubiquitin-Specific Peptidase 7

UN SDGs

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

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10.1016/j.molcel.2012.01.021

Cite this

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title = "ATM-dependent downregulation of USP7/HAUSP by PPM1G activates p53 response to DNA damage",

abstract = "The deubiquitylation enzyme USP7/HAUSP plays a major role in regulating genome stability and cancer prevention by controlling the key proteins involved in the DNA damage response. Despite this important role in controlling other proteins, USP7 itself has not been recognized as a target for regulation. Here, we report that USP7 regulation plays a central role in DNA damage signal transmission. We find that stabilization of Mdm2, and correspondingly p53 downregulation in unstressed cells, is accomplished by a specific isoform of USP7 (USP7S), which is phosphorylated at serine 18 by the protein kinase CK2. Phosphorylation stabilizes USP7S and thus contributes to Mdm2 stabilization and downregulation of p53. After ionizing radiation, dephosphorylation of USP7S by the ATM-dependent protein phosphatase PPM1G leads to USP7S downregulation, followed by Mdm2 downregulation and accumulation of p53. Our findings provide a quantitative transmission mechanism of the DNA damage signal to coordinate a p53-dependent DNA damage response.",

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author = "Khoronenkova, {Svetlana V} and Dianova, {Irina I} and Nicola Ternette and Kessler, {Benedikt M} and Parsons, {Jason L} and Dianov, {Grigory L}",

year = "2012",

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doi = "10.1016/j.molcel.2012.01.021",

language = "English",

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journal = "Molecular Cell",

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T1 - ATM-dependent downregulation of USP7/HAUSP by PPM1G activates p53 response to DNA damage

AU - Khoronenkova, Svetlana V

AU - Dianova, Irina I

AU - Ternette, Nicola

AU - Kessler, Benedikt M

AU - Parsons, Jason L

AU - Dianov, Grigory L

PY - 2012/3/30

Y1 - 2012/3/30

N2 - The deubiquitylation enzyme USP7/HAUSP plays a major role in regulating genome stability and cancer prevention by controlling the key proteins involved in the DNA damage response. Despite this important role in controlling other proteins, USP7 itself has not been recognized as a target for regulation. Here, we report that USP7 regulation plays a central role in DNA damage signal transmission. We find that stabilization of Mdm2, and correspondingly p53 downregulation in unstressed cells, is accomplished by a specific isoform of USP7 (USP7S), which is phosphorylated at serine 18 by the protein kinase CK2. Phosphorylation stabilizes USP7S and thus contributes to Mdm2 stabilization and downregulation of p53. After ionizing radiation, dephosphorylation of USP7S by the ATM-dependent protein phosphatase PPM1G leads to USP7S downregulation, followed by Mdm2 downregulation and accumulation of p53. Our findings provide a quantitative transmission mechanism of the DNA damage signal to coordinate a p53-dependent DNA damage response.

AB - The deubiquitylation enzyme USP7/HAUSP plays a major role in regulating genome stability and cancer prevention by controlling the key proteins involved in the DNA damage response. Despite this important role in controlling other proteins, USP7 itself has not been recognized as a target for regulation. Here, we report that USP7 regulation plays a central role in DNA damage signal transmission. We find that stabilization of Mdm2, and correspondingly p53 downregulation in unstressed cells, is accomplished by a specific isoform of USP7 (USP7S), which is phosphorylated at serine 18 by the protein kinase CK2. Phosphorylation stabilizes USP7S and thus contributes to Mdm2 stabilization and downregulation of p53. After ionizing radiation, dephosphorylation of USP7S by the ATM-dependent protein phosphatase PPM1G leads to USP7S downregulation, followed by Mdm2 downregulation and accumulation of p53. Our findings provide a quantitative transmission mechanism of the DNA damage signal to coordinate a p53-dependent DNA damage response.

KW - Amino Acid Sequence

KW - Ataxia Telangiectasia Mutated Proteins

KW - Casein Kinase II/genetics

KW - Cell Cycle Checkpoints

KW - Cell Cycle Proteins/genetics

KW - DNA Damage/physiology

KW - DNA-Binding Proteins/genetics

KW - Down-Regulation

KW - HeLa Cells/radiation effects

KW - Humans

KW - Molecular Sequence Data

KW - Phosphoprotein Phosphatases/genetics

KW - Phosphorylation

KW - Protein Phosphatase 2C

KW - Protein Serine-Threonine Kinases/genetics

KW - Proto-Oncogene Proteins c-mdm2/genetics

KW - Radiation, Ionizing

KW - Serine/metabolism

KW - Signal Transduction

KW - Tumor Suppressor Protein p53/genetics

KW - Tumor Suppressor Proteins/genetics

KW - Ubiquitin Thiolesterase/genetics

KW - Ubiquitin-Specific Peptidase 7

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DO - 10.1016/j.molcel.2012.01.021

M3 - Article

C2 - 22361354

SN - 1097-2765

VL - 45

SP - 801

EP - 813

JO - Molecular Cell

JF - Molecular Cell

IS - 6

ER -

ATM-dependent downregulation of USP7/HAUSP by PPM1G activates p53 response to DNA damage

Abstract

Bibliographical note

Keywords

UN SDGs

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