Proteomics Reveals Global Regulation of Protein SUMOylation by ATM and ATR Kinases during Replication Stress

TY - JOUR

T1 - Proteomics Reveals Global Regulation of Protein SUMOylation by ATM and ATR Kinases during Replication Stress

AU - Munk, Stephanie

AU - Sigurðsson, Jón Otti

AU - Xiao, Zhenyu

AU - Batth, Tanveer Singh

AU - Franciosa, Giulia

AU - von Stechow, Louise

AU - Lopez-Contreras, Andres Joaquin

AU - Vertegaal, Alfred Cornelis Otto

AU - Olsen, Jesper Velgaard

PY - 2017

Y1 - 2017

N2 - The mechanisms that protect eukaryotic DNA during the cumbersome task of replication depend on the precise coordination of several post-translational modification (PTM)-based signaling networks. Phosphorylation is a well-known regulator of the replication stress response, and recently an essential role for SUMOs (small ubiquitin-like modifiers) has also been established. Here, we investigate the global interplay between phosphorylation and SUMOylation in response to replication stress. Using SUMO and phosphoproteomic technologies, we identify thousands of regulated modification sites. We find co-regulation of central DNA damage and replication stress responders, of which the ATR-activating factor TOPBP1 is the most highly regulated. Using pharmacological inhibition of the DNA damage response kinases ATR and ATM, we find that these factors regulate global protein SUMOylation in the protein networks that protect DNA upon replication stress and fork breakage, pointing to integration between phosphorylation and SUMOylation in the cellular systems that protect DNA integrity. Munk et al. use mass spectrometry-based proteomics to analyze the interplay between SUMOylation and phosphorylation in replication stress. They analyze changes in the SUMO and phosphoproteome after MMC and hydroxyurea treatments and find that the DNA damage response kinases ATR and ATM globally regulate SUMOylation upon replication stress and fork breakage.

AB - The mechanisms that protect eukaryotic DNA during the cumbersome task of replication depend on the precise coordination of several post-translational modification (PTM)-based signaling networks. Phosphorylation is a well-known regulator of the replication stress response, and recently an essential role for SUMOs (small ubiquitin-like modifiers) has also been established. Here, we investigate the global interplay between phosphorylation and SUMOylation in response to replication stress. Using SUMO and phosphoproteomic technologies, we identify thousands of regulated modification sites. We find co-regulation of central DNA damage and replication stress responders, of which the ATR-activating factor TOPBP1 is the most highly regulated. Using pharmacological inhibition of the DNA damage response kinases ATR and ATM, we find that these factors regulate global protein SUMOylation in the protein networks that protect DNA upon replication stress and fork breakage, pointing to integration between phosphorylation and SUMOylation in the cellular systems that protect DNA integrity. Munk et al. use mass spectrometry-based proteomics to analyze the interplay between SUMOylation and phosphorylation in replication stress. They analyze changes in the SUMO and phosphoproteome after MMC and hydroxyurea treatments and find that the DNA damage response kinases ATR and ATM globally regulate SUMOylation upon replication stress and fork breakage.

KW - ATM

KW - ATR

KW - hydroxyurea

KW - kinase inhibitors

KW - MMC

KW - phosphoproteomics

KW - quantitative proteomics

KW - Replication stress

KW - SUMO

KW - TOPBP1

U2 - 10.1016/j.celrep.2017.09.059

DO - 10.1016/j.celrep.2017.09.059

M3 - Journal article

C2 - 29020638

AN - SCOPUS:85030845585

SN - 2639-1856

VL - 21

SP - 546

EP - 558

JO - Cell Reports

JF - Cell Reports

IS - 2

ER -