title: FBW7 regulates DNA interstrand cross-link repair by modulating FAAP20 degradation.
abstract: Mutations that deregulate protein degradation lead to human malignancies. The SCF ubiquitin E3 ligase complex degrades key oncogenic regulators, thereby limiting their oncogenic potential. FBW7 is a substrate recognition subunit of SCFFBW7 and is among the most commonly mutated ubiquitin-proteasome system proteins in cancer. FBW7-mutated cancer cells display increased genome instability, but the molecular mechanism by which FBW7 preserves genome integrity remains elusive. Here, we demonstrate that SCFFBW7 regulates the stability of FAAP20, a critical component of the Fanconi anemia (FA) DNA interstrand cross-link (ICL) repair pathway. Phosphorylation of the FAAP20 degron motif by GSK3β provides a platform for recognition and polyubiquitination of FAAP20 by FBW7, and its subsequent degradation by the proteasome. Accordingly, enhanced GSK3β-FBW7 signaling disrupts the FA pathway. In cells expressing non-phosphorylatable FAAP20 mutant, the turnover of its binding partner, FANCA, is deregulated in the chromatin during DNA ICL repair, and the FA pathway is compromised. We propose that FAAP20 degradation, which is prompted by its phosphorylation, controls the dynamics of the FA core complex required for completing DNA ICL repair. Together, this study provides insights into how FBW7-mediated proteolysis regulates genome stability and how its deregulation is associated with tumorigenesis.
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York, USA.
authors.forename: Jingming
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York, USA.
authors.forename: Ukhyun
authors.initials: U
authors.lastname: Jo
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York, USA.
authors.forename: So Young
authors.initials: SY
authors.lastname: Joo
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York, USA.
authors.forename: Hyungjin
authors.initials: H
authors.lastname: Kim
mesh_terms: D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D000073979:F-Box-WD Repeat-Containing Protein 7 / Q000235:genetics / Q000378:metabolism*; D051856:Fanconi Anemia Complementation Group Proteins / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D042822:Genomic Instability; D000071679:Glycogen Synthase Kinase 3 beta / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053858:Metabolic Networks and Pathways; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism*; D015398:Signal Transduction; D054875:Ubiquitination
chemical_list: D000073979:F-Box-WD Repeat-Containing Protein 7; C570807:FAAP20 protein, human; C513273:FBXW7 protein, human; D051856:Fanconi Anemia Complementation Group Proteins; D034741:RNA, Small Interfering; D044843:SKP Cullin F-Box Protein Ligases; D000071679:Glycogen Synthase Kinase 3 beta; D046988:Proteasome Endopeptidase Complex
keywords: Chromosome Section; FBW7; Fanconi anemia; genome instability; tumor suppressor; ubiquitin-proteasome system