TY - JOUR
T1 - Post-Translational Dosage Compensation Buffers Genetic Perturbations to Stoichiometry of Protein Complexes
AU - Ishikawa, Koji
AU - Makanae, Koji
AU - Iwasaki, Shintaro
AU - Ingolia, Nicholas T.
AU - Moriya, Hisao
N1 - Funding Information:
This work was supported by a JSPS Grant-in-Aid for Scientific Research (B) (26290069) (HM), a Grant-in-Aid for JSPS Research Fellow (16J00852) (KI), and a grant from the National Institute of Environmental Health Sciences (R21ES22575) (NTI). SI is supported by a Human Frontier Science Program long-term fellowship. This work used the Vincent J. Coates Genomics Sequencing Laboratory at UC Berkeley, supported by NIH S10 Instrumentation Grant (OD018174). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We would like to thank the Vincent J. Coates Genomics Sequencing Laboratory at the University of California, Berkeley, for help with deep sequencing. We also would like to thank the National Bio-Resource Project in Japan for providing CMY765 strain (NBRP ID: BY22813). We thank Dr. Yuki Shimizu-Yoshida for providing strains. We also thank members of the Moriya and Ingolia laboratories for advice and helpful discussions.
Publisher Copyright:
© 2017 Ishikawa et al.
PY - 2017/1
Y1 - 2017/1
N2 - Understanding buffering mechanisms for various perturbations is essential for understanding robustness in cellular systems. Protein-level dosage compensation, which arises when changes in gene copy number do not translate linearly into protein level, is one mechanism for buffering against genetic perturbations. Here, we present an approach to identify genes with dosage compensation by increasing the copy number of individual genes using the genetic tug-of-war technique. Our screen of chromosome I suggests that dosage-compensated genes constitute approximately 10% of the genome and consist predominantly of subunits of multi-protein complexes. Importantly, because subunit levels are regulated in a stoichiometry-dependent manner, dosage compensation plays a crucial role in maintaining subunit stoichiometries. Indeed, we observed changes in the levels of a complex when its subunit stoichiometries were perturbed. We further analyzed compensation mechanisms using a proteasome-defective mutant as well as ribosome profiling, which provided strong evidence for compensation by ubiquitin-dependent degradation but not reduced translational efficiency. Thus, our study provides a systematic understanding of dosage compensation and highlights that this post-translational regulation is a critical aspect of robustness in cellular systems.
AB - Understanding buffering mechanisms for various perturbations is essential for understanding robustness in cellular systems. Protein-level dosage compensation, which arises when changes in gene copy number do not translate linearly into protein level, is one mechanism for buffering against genetic perturbations. Here, we present an approach to identify genes with dosage compensation by increasing the copy number of individual genes using the genetic tug-of-war technique. Our screen of chromosome I suggests that dosage-compensated genes constitute approximately 10% of the genome and consist predominantly of subunits of multi-protein complexes. Importantly, because subunit levels are regulated in a stoichiometry-dependent manner, dosage compensation plays a crucial role in maintaining subunit stoichiometries. Indeed, we observed changes in the levels of a complex when its subunit stoichiometries were perturbed. We further analyzed compensation mechanisms using a proteasome-defective mutant as well as ribosome profiling, which provided strong evidence for compensation by ubiquitin-dependent degradation but not reduced translational efficiency. Thus, our study provides a systematic understanding of dosage compensation and highlights that this post-translational regulation is a critical aspect of robustness in cellular systems.
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U2 - 10.1371/journal.pgen.1006554
DO - 10.1371/journal.pgen.1006554
M3 - Article
C2 - 28121980
AN - SCOPUS:85011421250
VL - 13
JO - PLoS Genetics
JF - PLoS Genetics
SN - 1553-7390
IS - 1
M1 - e1006554
ER -
