Year: 2016
Type: article
Abstract: // Jingming Wang 1 , Ukhyun Jo 1 , So Young Joo 1 and Hyungjin Kim 1 1 Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York, USA Correspondence to: Hyungjin Kim, email: // Keywords : Fanconi anemia, ubiquitin-proteasome system, FBW7, genome instability, tumor suppressor, Chromosome Section Received : January 25, 2016 Accepted : May 16, 2016 Published : May 25, 2016 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 SCF FBW7 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 SCF FBW7 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.
Source: Oncotarget
Authors: Jingming Wang, Ukhyun Jo, So Young Joo, Hyungjin Kim
Institution: Stony Brook University
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: diamond
Funder: Stony Brook University
OpenAlex ID: W2403774978