FBW7 Loss Promotes Chromosomal Instability and Tumorigenesis via Cyclin E1/CDK2–Mediated Phosphorylation of CENP-A

Abstract

The centromere regulates proper chromosome segregation and its dysfunction is implicated in chromosomal instability (CIN). However, relatively little is known about how centromere dysfunction occurs in cancer. Here we define the consequences of phosphorylation by Cyclin E1/CDK2 on a conserved Ser18 residue of centromere-associated protein CENP-A, an essential histone H3 variant that specifies centromere identity. Ser18 hyperphosphorylation in cells occurred upon loss of FBW7, a tumor suppressor whose inactivation leads to chromosomal instability (CIN). This event on CENP-A reduced its centromeric localization, increased CIN and promoted anchorage-independent growth and xenograft tumor formation. Overall, our results revealed a pathway that Cyclin E1/CDK2 activation coupled with FBW7 loss promotes CIN and tumor progression via CENP-A-mediated centromere dysfunction.

Posttranslational mechanisms controlling centromere function and assembly

“…CENP-A Ser18 is a substrate for cyclinE1/CDK2 phosphorylation, and is cell cycle regulated [11]. Loss of phosphorylation or hyper-phosphorylation at these sites, lead to chromosome missegregation [10,11].…”

“…CENP-A Ser18 is a substrate for cyclinE1/CDK2 phosphorylation, and is cell cycle regulated [11]. Loss of phosphorylation or hyper-phosphorylation at these sites, lead to chromosome missegregation [10,11]. In vitro studies suggest that CENP-A has the ability to form a salt-bridged secondary structure through intramolecular association, which is dependent on phosphorylation of Ser16/18, and therefore this dual phosphorylation may impact the higher order chromatin organization of the centromere [10].…”

Posttranslational modifications of CENP-A: marks of distinction

“…More recently, another modification, Ser-18 phosphorylation that also exists outside CATD has been shown to negatively regulate CENP-A deposition (Takada et al 2017). Modifications on histone H4 present in the prenucleosomal complex are also involved in CENP-A deposition.…”

“…Similar to Ser-68, Ser-18 is also not essential for CENP-A deposition, but Ser-18 phosphorylation by Cyclin E/CDK2 complex appears to negatively regulate centromeric localization of CENP-A (Takada et al 2017). Given that Cyclin E levels remain low during mitosis to G 1 transition, a hypophosphorylated state of Ser-18 may facilitate the specific timing of CENP-A deposition at centromeres in G 1 phase.…”

“…Growing evidence suggests the potential alteration of CENP-A PTMs associated with cancer progression. The observation that a CENP-A methylation defective mutant together with loss of p53 , promotes tumor development in nude mice and the correlation of Ser-18 hyperphophorylation with cyclin E-driven tumors, indicate a potential role of CENP-A modifications in cancer (Sathyan et al 2017; Takada et al 2017). Large-scale proteomic studies have revealed several additional modifications; the biological relevance of which is yet to be discovered (please see http://www.phosphositeplus.com).…”