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.
Highlights
The ubiquitin-proteasome system (UPS) regulates a broad range of cellular processes by governing the cellular levels of key regulatory proteins [1]
As the FANCA-FAAP20 interaction is essential for maintaining the functional Fanconi anemia (FA) core complex, we sought to determine how the interaction dynamics are regulated, which could dictate the efficiency of DNA interstrand cross-link (ICL) repair
Measuring the half-life of FANCA and FAAP20 by the cycloheximide (CHX) blocking assay showed that FAAP20 is rapidly degraded compared with FANCA, which exhibits a longer half-life, indicating that FAAP20 turnover should be tightly regulated to www.impactjournals.com/oncotarget maintain FANCA stability (Figure 1A, 1B)
Summary
The ubiquitin-proteasome system (UPS) regulates a broad range of cellular processes by governing the cellular levels of key regulatory proteins [1]. Disrupting balanced levels of oncoproteins or tumor suppressors by either loss of Ub E3 ligase or enhanced deubiquitinating enzyme (DUB) activity provides cancer cells with a survival advantage. FBW7 (F-box and WD repeat domain-containing 7, called cell division cycle mutant 4, Cdc, in budding yeast) is a substrate recognition unit of the SCF (SKP1-CUL1F-box protein) ubiquitin E3 ligase complex, SCFFBW7, a member of Cullin-RING finger domain-containing E3 ligase [6]. FBW7 recognizes its substrates when they are phosphorylated within the so-called Cdc phospho-degron (CPD) motif, which consists of the amino acid sequence L-X-pS/pT(0)P-X-X-pS/pT(+4) [10,11,12,13]. Phosphorylation of the CPD motif determines the context of substrate degradation by SCFFBW7; in many cases, glycogen synthase kinase www.impactjournals.com/oncotarget
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