title: DNA Damage Regulates Translation through β-TRCP Targeting of CReP.
abstract: The Skp1-Cul1-F box complex (SCF) associates with any one of a number of F box proteins, which serve as substrate binding adaptors. The human F box protein βTRCP directs the conjugation of ubiquitin to a variety of substrate proteins, leading to the destruction of the substrate by the proteasome. To identify βTRCP substrates, we employed a recently-developed technique, called Ligase Trapping, wherein a ubiquitin ligase is fused to a ubiquitin-binding domain to "trap" ubiquitinated substrates. 88% of the candidate substrates that we examined were bona fide substrates, comprising twelve previously validated substrates, eleven new substrates and three false positives. One βTRCP substrate, CReP, is a Protein Phosphatase 1 (PP1) specificity subunit that targets the translation initiation factor eIF2α to promote the removal of a stress-induced inhibitory phosphorylation and increase cap-dependent translation. We found that CReP is targeted by βTRCP for degradation upon DNA damage. Using a stable CReP allele, we show that depletion of CReP is required for the full induction of eIF2α phosphorylation upon DNA damage, and contributes to keeping the levels of translation low as cells recover from DNA damage.
authors.affiliation: Department of Biochemistry and Biophysics, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Theresa B
authors.initials: TB
authors.lastname: Loveless
authors.affiliation: Department of Biochemistry and Biophysics, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Topacio
authors.affiliation: Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Ajay A
authors.initials: AA
authors.lastname: Vashisht
authors.affiliation: Department of Biochemistry and Biophysics, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Shastyn
authors.initials: S
authors.lastname: Galaang
authors.affiliation: Department of Biochemistry and Biophysics, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Katie M
authors.initials: KM
authors.lastname: Ulrich
authors.affiliation: Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Young
authors.affiliation: Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: James A
authors.initials: JA
authors.lastname: Wohlschlegel
authors.affiliation: Department of Biochemistry and Biophysics, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: David P
authors.initials: DP
authors.lastname: Toczyski
mesh_terms: D000818:Animals; D004249:DNA Damage; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D011485:Protein Binding; D014176:Protein Biosynthesis; D054645:Protein Phosphatase 1 / Q000378:metabolism*; D055550:Protein Stability; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism*
chemical_list: C471644:BTRC protein, human; D044844:beta-Transducin Repeat-Containing Proteins; D054645:Protein Phosphatase 1