APC/CCdh1 is required for the termination of chromosomal passenger complex activity upon mitotic exit.

Takaaki Tsunematsu,William C Earnshaw,Hidehiko Kawai,Koichi Tsuneyama,Rieko Arakaki,Jan Ruppert,Naozumi Ishimaru,Michele Pagano,Yasusei Kudo

doi:10.1242/jcs.251314

Abstract

ABSTRACTDuring mitosis, the chromosomal passenger complex (CPC) ensures the faithful transmission of the genome. The CPC is composed of the enzymatic component Aurora B (AURKB) and the three regulatory and targeting components borealin, INCENP, and survivin (also known as BIRC5). Although the CPC is known to be involved in diverse mitotic events, it is still unclear how CPC function terminates after mitosis. Here we show that borealin is ubiquitylated by the anaphase promoting complex/cyclosome (APC/C) and its cofactor Cdh1 (also known as FZR1) and is subsequently degraded in G1 phase. Cdh1 binds to regions within the N terminus of borealin that act as a non-canonical degron. Aurora B has also been shown previously to be degraded by the APC/CCdh1 from late mitosis to G1. Indeed, Cdh1 depletion sustains an Aurora B activity with stable levels of borealin and Aurora B throughout the cell cycle, and causes reduced efficiency of DNA replication after release from serum starvation. Notably, inhibition of Aurora B kinase activity improves the efficiency of DNA replication in Cdh1-depleted cells. We thus propose that APC/CCdh1 terminates CPC activity upon mitotic exit and thereby contributes to proper control of DNA replication.

Highlights

The chromosomal passenger complex (CPC) plays an important role during mitosis to ensure the faithful segregation of genetic material into daughter cells (Earnshaw and Bernat, 1991)
Borealin protein is degraded via APC/CCdh1 during G1 Borealin protein levels oscillate during the cell cycle; the protein accumulates during G2 and M phases and disappears in G1 (Fig. 1A,B)
We examined the involvement of the ubiquitin– proteasome system (UPS) in the regulation of borealin protein levels during the cell cycle

Summary

Introduction

The chromosomal passenger complex (CPC) plays an important role during mitosis to ensure the faithful segregation of genetic material into daughter cells (Earnshaw and Bernat, 1991). The CPC consists of four proteins: Aurora B (AURKB), INCENP (inner centromere protein), borealin ( known as CDCA8 and DASRA). Borealin depletion by RNA interference increases the percentage of prometaphase cells (Bekier et al, 2015) and results in a dramatic increase in spindle–kinetochore misattachments and failures in cytokinesis (Gassmann et al, 2004; Sampath et al, 2004). These and a host of other observations indicate that the CPC regulates mitosis. It is still unclear how CPC activity is terminated after mitosis

Methods

Results

Conclusion