Acetylation of PCNA Sliding Surface by Eco1 Promotes Genome Stability through Homologous Recombination

Pierre Billon; Jian Li; Jean Philippe Lambert; Yizhang Chen; Véronique Tremblay; Joseph S. Brunzelle; Anne Claude Gingras; Alain Verreault; Tomohiko Sugiyama; Jean Francois Couture; Jacques Côté

doi:10.1016/j.molcel.2016.10.033

Acetylation of PCNA Sliding Surface by Eco1 Promotes Genome Stability through Homologous Recombination

Pierre Billon, Jian Li, Jean Philippe Lambert, Yizhang Chen, Véronique Tremblay, Joseph S. Brunzelle, Anne Claude Gingras, Alain Verreault, Tomohiko Sugiyama, Jean Francois Couture, Jacques Côté^*

^*Corresponding author for this work

Pharmacology

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

36 Scopus citations

Abstract

During DNA replication, proliferating cell nuclear antigen (PCNA) adopts a ring-shaped structure to promote processive DNA synthesis, acting as a sliding clamp for polymerases. Known posttranslational modifications function at the outer surface of the PCNA ring to favor DNA damage bypass. Here, we demonstrate that acetylation of lysine residues at the inner surface of PCNA is induced by DNA lesions. We show that cohesin acetyltransferase Eco1 targets lysine 20 at the sliding surface of the PCNA ring in vitro and in vivo in response to DNA damage. Mimicking constitutive acetylation stimulates homologous recombination and robustly suppresses the DNA damage sensitivity of mutations in damage tolerance pathways. In comparison to the unmodified trimer, structural differences are observed at the interface between protomers in the crystal structure of the PCNA-K20ac ring. Thus, acetylation regulates PCNA sliding on DNA in the presence of DNA damage, favoring homologous recombination linked to sister-chromatid cohesion.

Original language	English (US)
Pages (from-to)	78-90
Number of pages	13
Journal	Molecular cell
Volume	65
Issue number	1
DOIs	https://doi.org/10.1016/j.molcel.2016.10.033
State	Published - Jan 5 2017

Funding

We thank members of the J.C. lab, Alberto Ciccia, and Damien D'Amours for comments on the manuscript. We are grateful to Helle Ulrich for the anti-Pol30 antibody and advice, to Jason Chin for the system to purify acetylated recombinant PCNA, and to Stefan Jentsch and Jennifer Gerton for sharing plasmids and strains. This work was supported by grants from the Canadian Institutes of Health Research (CIHR) to A.-C.G. (MOP-123322), J.-F.C. (MOP-136816), and J.C. (MOP-14308; FDN-143314). J.-P.L. was supported by CIHR and TD Bank Health Research Fellowships. A.-C.G. holds the Lea Reichmann Chair in Cancer Proteomics. A.-C.G., J.-F.C., and J.C. hold the Canada Research Chairs in Functional Proteomics, Structural Biology and Epigenetics, and Chromatin Biology and Molecular Epigenetics, respectively.

Keywords

DNA polymerases
Eco1
PCNA
homologous recombination
lysine acetylation
translesion synthesis

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2016.10.033

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title = "Acetylation of PCNA Sliding Surface by Eco1 Promotes Genome Stability through Homologous Recombination",

abstract = "During DNA replication, proliferating cell nuclear antigen (PCNA) adopts a ring-shaped structure to promote processive DNA synthesis, acting as a sliding clamp for polymerases. Known posttranslational modifications function at the outer surface of the PCNA ring to favor DNA damage bypass. Here, we demonstrate that acetylation of lysine residues at the inner surface of PCNA is induced by DNA lesions. We show that cohesin acetyltransferase Eco1 targets lysine 20 at the sliding surface of the PCNA ring in vitro and in vivo in response to DNA damage. Mimicking constitutive acetylation stimulates homologous recombination and robustly suppresses the DNA damage sensitivity of mutations in damage tolerance pathways. In comparison to the unmodified trimer, structural differences are observed at the interface between protomers in the crystal structure of the PCNA-K20ac ring. Thus, acetylation regulates PCNA sliding on DNA in the presence of DNA damage, favoring homologous recombination linked to sister-chromatid cohesion.",

keywords = "DNA polymerases, Eco1, PCNA, homologous recombination, lysine acetylation, translesion synthesis",

author = "Pierre Billon and Jian Li and Lambert, {Jean Philippe} and Yizhang Chen and V{\'e}ronique Tremblay and Brunzelle, {Joseph S.} and Gingras, {Anne Claude} and Alain Verreault and Tomohiko Sugiyama and Couture, {Jean Francois} and Jacques C{\^o}t{\'e}",

note = "Funding Information: We thank members of the J.C. lab, Alberto Ciccia, and Damien D'Amours for comments on the manuscript. We are grateful to Helle Ulrich for the anti-Pol30 antibody and advice, to Jason Chin for the system to purify acetylated recombinant PCNA, and to Stefan Jentsch and Jennifer Gerton for sharing plasmids and strains. This work was supported by grants from the Canadian Institutes of Health Research (CIHR) to A.-C.G. (MOP-123322), J.-F.C. (MOP-136816), and J.C. (MOP-14308; FDN-143314). J.-P.L. was supported by CIHR and TD Bank Health Research Fellowships. A.-C.G. holds the Lea Reichmann Chair in Cancer Proteomics. A.-C.G., J.-F.C., and J.C. hold the Canada Research Chairs in Functional Proteomics, Structural Biology and Epigenetics, and Chromatin Biology and Molecular Epigenetics, respectively. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",

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doi = "10.1016/j.molcel.2016.10.033",

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T1 - Acetylation of PCNA Sliding Surface by Eco1 Promotes Genome Stability through Homologous Recombination

AU - Billon, Pierre

AU - Li, Jian

AU - Lambert, Jean Philippe

AU - Chen, Yizhang

AU - Tremblay, Véronique

AU - Brunzelle, Joseph S.

AU - Gingras, Anne Claude

AU - Verreault, Alain

AU - Sugiyama, Tomohiko

AU - Couture, Jean Francois

AU - Côté, Jacques

N1 - Funding Information: We thank members of the J.C. lab, Alberto Ciccia, and Damien D'Amours for comments on the manuscript. We are grateful to Helle Ulrich for the anti-Pol30 antibody and advice, to Jason Chin for the system to purify acetylated recombinant PCNA, and to Stefan Jentsch and Jennifer Gerton for sharing plasmids and strains. This work was supported by grants from the Canadian Institutes of Health Research (CIHR) to A.-C.G. (MOP-123322), J.-F.C. (MOP-136816), and J.C. (MOP-14308; FDN-143314). J.-P.L. was supported by CIHR and TD Bank Health Research Fellowships. A.-C.G. holds the Lea Reichmann Chair in Cancer Proteomics. A.-C.G., J.-F.C., and J.C. hold the Canada Research Chairs in Functional Proteomics, Structural Biology and Epigenetics, and Chromatin Biology and Molecular Epigenetics, respectively. Publisher Copyright: © 2017 Elsevier Inc.

PY - 2017/1/5

Y1 - 2017/1/5

N2 - During DNA replication, proliferating cell nuclear antigen (PCNA) adopts a ring-shaped structure to promote processive DNA synthesis, acting as a sliding clamp for polymerases. Known posttranslational modifications function at the outer surface of the PCNA ring to favor DNA damage bypass. Here, we demonstrate that acetylation of lysine residues at the inner surface of PCNA is induced by DNA lesions. We show that cohesin acetyltransferase Eco1 targets lysine 20 at the sliding surface of the PCNA ring in vitro and in vivo in response to DNA damage. Mimicking constitutive acetylation stimulates homologous recombination and robustly suppresses the DNA damage sensitivity of mutations in damage tolerance pathways. In comparison to the unmodified trimer, structural differences are observed at the interface between protomers in the crystal structure of the PCNA-K20ac ring. Thus, acetylation regulates PCNA sliding on DNA in the presence of DNA damage, favoring homologous recombination linked to sister-chromatid cohesion.

AB - During DNA replication, proliferating cell nuclear antigen (PCNA) adopts a ring-shaped structure to promote processive DNA synthesis, acting as a sliding clamp for polymerases. Known posttranslational modifications function at the outer surface of the PCNA ring to favor DNA damage bypass. Here, we demonstrate that acetylation of lysine residues at the inner surface of PCNA is induced by DNA lesions. We show that cohesin acetyltransferase Eco1 targets lysine 20 at the sliding surface of the PCNA ring in vitro and in vivo in response to DNA damage. Mimicking constitutive acetylation stimulates homologous recombination and robustly suppresses the DNA damage sensitivity of mutations in damage tolerance pathways. In comparison to the unmodified trimer, structural differences are observed at the interface between protomers in the crystal structure of the PCNA-K20ac ring. Thus, acetylation regulates PCNA sliding on DNA in the presence of DNA damage, favoring homologous recombination linked to sister-chromatid cohesion.

KW - DNA polymerases

KW - Eco1

KW - PCNA

KW - homologous recombination

KW - lysine acetylation

KW - translesion synthesis

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JO - Molecular cell

JF - Molecular cell

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ER -

Acetylation of PCNA Sliding Surface by Eco1 Promotes Genome Stability through Homologous Recombination

Abstract

Funding

Keywords

ASJC Scopus subject areas

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