PRMT5-Dependent Methylation of the TIP60 Coactivator RUVBL1 Is a Key Regulator of Homologous Recombination

Thomas L Clarke; Maria Pilar Sanchez-Bailon; Kelly Chiang; John J Reynolds; Joaquin Herrero-Ruiz; Tiago M Bandeiras; Pedro M Matias; Sarah L Maslen; J Mark Skehel; Grant S Stewart; Clare C Davies

doi:10.1016/j.molcel.2017.01.019

PRMT5-Dependent Methylation of the TIP60 Coactivator RUVBL1 Is a Key Regulator of Homologous Recombination

Thomas L Clarke, Maria Pilar Sanchez-Bailon, Kelly Chiang, John J Reynolds, Joaquin Herrero-Ruiz, Tiago M Bandeiras, Pedro M Matias, Sarah L Maslen, J Mark Skehel, Grant S Stewart, Clare C Davies

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

Abstract

Protein post-translation modification plays an important role in regulating DNA repair; however, the role of arginine methylation in this process is poorly understood. Here we identify the arginine methyltransferase PRMT5 as a key regulator of homologous recombination (HR)-mediated double-strand break (DSB) repair, which is mediated through its ability to methylate RUVBL1, a cofactor of the TIP60 complex. We show that PRMT5 targets RUVBL1 for methylation at position R205, which facilitates TIP60-dependent mobilization of 53BP1 from DNA breaks, promoting HR. Mechanistically, we demonstrate that PRMT5-directed methylation of RUVBL1 is critically required for the acetyltransferase activity of TIP60, promoting histone H4K16 acetylation, which facilities 53BP1 displacement from DSBs. Interestingly, RUVBL1 methylation did not affect the ability of TIP60 to facilitate ATM activation. Taken together, our findings reveal the importance of PRMT5-mediated arginine methylation during DSB repair pathway choice through its ability to regulate acetylation-dependent control of 53BP1 localization.

Original language	English
Pages (from-to)	900-916.e7
Number of pages	25
Journal	Molecular Cell
Volume	65
Issue number	5
Early online date	23 Feb 2017
DOIs	https://doi.org/10.1016/j.molcel.2017.01.019
Publication status	Published - 2 Mar 2017

Keywords

ATPases Associated with Diverse Cellular Activities
Acetylation
Animals
Arginine
Ataxia Telangiectasia Mutated Proteins/metabolism
Carrier Proteins/genetics
DNA Breaks, Double-Stranded
DNA Helicases/genetics
Genomic Instability
HEK293 Cells
HeLa Cells
Histone Acetyltransferases/genetics
Histones/metabolism
Humans
Lysine Acetyltransferase 5
Methylation
Mice
Mice, Transgenic
Protein Processing, Post-Translational
Protein-Arginine N-Methyltransferases/genetics
RNA Interference
Recombinational DNA Repair
Time Factors
Transfection
Tumor Suppressor p53-Binding Protein 1/genetics

Access to Document

10.1016/j.molcel.2017.01.019Licence: CC BY 4.0

Cite this

Clarke, T. L., Sanchez-Bailon, M. P., Chiang, K., Reynolds, J. J., Herrero-Ruiz, J., Bandeiras, T. M., Matias, P. M., Maslen, S. L., Skehel, J. M., Stewart, G. S., & Davies, C. C. (2017). PRMT5-Dependent Methylation of the TIP60 Coactivator RUVBL1 Is a Key Regulator of Homologous Recombination. Molecular Cell, 65(5), 900-916.e7. https://doi.org/10.1016/j.molcel.2017.01.019

@article{385a6206aa27493b87cf66ea063bd41f,

title = "PRMT5-Dependent Methylation of the TIP60 Coactivator RUVBL1 Is a Key Regulator of Homologous Recombination",

abstract = "Protein post-translation modification plays an important role in regulating DNA repair; however, the role of arginine methylation in this process is poorly understood. Here we identify the arginine methyltransferase PRMT5 as a key regulator of homologous recombination (HR)-mediated double-strand break (DSB) repair, which is mediated through its ability to methylate RUVBL1, a cofactor of the TIP60 complex. We show that PRMT5 targets RUVBL1 for methylation at position R205, which facilitates TIP60-dependent mobilization of 53BP1 from DNA breaks, promoting HR. Mechanistically, we demonstrate that PRMT5-directed methylation of RUVBL1 is critically required for the acetyltransferase activity of TIP60, promoting histone H4K16 acetylation, which facilities 53BP1 displacement from DSBs. Interestingly, RUVBL1 methylation did not affect the ability of TIP60 to facilitate ATM activation. Taken together, our findings reveal the importance of PRMT5-mediated arginine methylation during DSB repair pathway choice through its ability to regulate acetylation-dependent control of 53BP1 localization.",

keywords = "ATPases Associated with Diverse Cellular Activities, Acetylation, Animals, Arginine, Ataxia Telangiectasia Mutated Proteins/metabolism, Carrier Proteins/genetics, DNA Breaks, Double-Stranded, DNA Helicases/genetics, Genomic Instability, HEK293 Cells, HeLa Cells, Histone Acetyltransferases/genetics, Histones/metabolism, Humans, Lysine Acetyltransferase 5, Methylation, Mice, Mice, Transgenic, Protein Processing, Post-Translational, Protein-Arginine N-Methyltransferases/genetics, RNA Interference, Recombinational DNA Repair, Time Factors, Transfection, Tumor Suppressor p53-Binding Protein 1/genetics",

author = "Clarke, {Thomas L} and Sanchez-Bailon, {Maria Pilar} and Kelly Chiang and Reynolds, {John J} and Joaquin Herrero-Ruiz and Bandeiras, {Tiago M} and Matias, {Pedro M} and Maslen, {Sarah L} and Skehel, {J Mark} and Stewart, {Grant S} and Davies, {Clare C}",

year = "2017",

month = mar,

day = "2",

doi = "10.1016/j.molcel.2017.01.019",

language = "English",

volume = "65",

pages = "900--916.e7",

journal = "Molecular Cell",

issn = "1097-2765",

publisher = "Cell Press",

number = "5",

}

TY - JOUR

T1 - PRMT5-Dependent Methylation of the TIP60 Coactivator RUVBL1 Is a Key Regulator of Homologous Recombination

AU - Clarke, Thomas L

AU - Sanchez-Bailon, Maria Pilar

AU - Chiang, Kelly

AU - Reynolds, John J

AU - Herrero-Ruiz, Joaquin

AU - Bandeiras, Tiago M

AU - Matias, Pedro M

AU - Maslen, Sarah L

AU - Skehel, J Mark

AU - Stewart, Grant S

AU - Davies, Clare C

PY - 2017/3/2

Y1 - 2017/3/2

N2 - Protein post-translation modification plays an important role in regulating DNA repair; however, the role of arginine methylation in this process is poorly understood. Here we identify the arginine methyltransferase PRMT5 as a key regulator of homologous recombination (HR)-mediated double-strand break (DSB) repair, which is mediated through its ability to methylate RUVBL1, a cofactor of the TIP60 complex. We show that PRMT5 targets RUVBL1 for methylation at position R205, which facilitates TIP60-dependent mobilization of 53BP1 from DNA breaks, promoting HR. Mechanistically, we demonstrate that PRMT5-directed methylation of RUVBL1 is critically required for the acetyltransferase activity of TIP60, promoting histone H4K16 acetylation, which facilities 53BP1 displacement from DSBs. Interestingly, RUVBL1 methylation did not affect the ability of TIP60 to facilitate ATM activation. Taken together, our findings reveal the importance of PRMT5-mediated arginine methylation during DSB repair pathway choice through its ability to regulate acetylation-dependent control of 53BP1 localization.

AB - Protein post-translation modification plays an important role in regulating DNA repair; however, the role of arginine methylation in this process is poorly understood. Here we identify the arginine methyltransferase PRMT5 as a key regulator of homologous recombination (HR)-mediated double-strand break (DSB) repair, which is mediated through its ability to methylate RUVBL1, a cofactor of the TIP60 complex. We show that PRMT5 targets RUVBL1 for methylation at position R205, which facilitates TIP60-dependent mobilization of 53BP1 from DNA breaks, promoting HR. Mechanistically, we demonstrate that PRMT5-directed methylation of RUVBL1 is critically required for the acetyltransferase activity of TIP60, promoting histone H4K16 acetylation, which facilities 53BP1 displacement from DSBs. Interestingly, RUVBL1 methylation did not affect the ability of TIP60 to facilitate ATM activation. Taken together, our findings reveal the importance of PRMT5-mediated arginine methylation during DSB repair pathway choice through its ability to regulate acetylation-dependent control of 53BP1 localization.

KW - ATPases Associated with Diverse Cellular Activities

KW - Acetylation

KW - Animals

KW - Arginine

KW - Ataxia Telangiectasia Mutated Proteins/metabolism

KW - Carrier Proteins/genetics

KW - DNA Breaks, Double-Stranded

KW - DNA Helicases/genetics

KW - Genomic Instability

KW - HEK293 Cells

KW - HeLa Cells

KW - Histone Acetyltransferases/genetics

KW - Histones/metabolism

KW - Humans

KW - Lysine Acetyltransferase 5

KW - Methylation

KW - Mice

KW - Mice, Transgenic

KW - Protein Processing, Post-Translational

KW - Protein-Arginine N-Methyltransferases/genetics

KW - RNA Interference

KW - Recombinational DNA Repair

KW - Time Factors

KW - Transfection

KW - Tumor Suppressor p53-Binding Protein 1/genetics

UR - https://www.cell.com/molecular-cell/fulltext/S1097-2765(17)30045-X

U2 - 10.1016/j.molcel.2017.01.019

DO - 10.1016/j.molcel.2017.01.019

M3 - Article

C2 - 28238654

SN - 1097-2765

VL - 65

SP - 900-916.e7

JO - Molecular Cell

JF - Molecular Cell

IS - 5

ER -

PRMT5-Dependent Methylation of the TIP60 Coactivator RUVBL1 Is a Key Regulator of Homologous Recombination

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this