PRMT1 promotes mitosis of cancer cells through arginine methylation of INCENP.

Xiaolan Deng,Gottfried Von Keudell,Naoshi Dohmae,Ryuji Hamamoto,Makoto Nakakido,Takehiro Suzuki,Yuichiro Yoshioka,Yusuke Nakamura,Lianhua Piao

doi:10.18632/oncotarget.6050

Xiaolan Deng, Gottfried Von Keudell + Show 7 more

Open Access

https://doi.org/10.18632/oncotarget.6050

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Abstract

Inner centromere protein (INCENP) is a part of a protein complex known as the chromosomal passenger complex (CPC) that is essential for correcting non-bipolar chromosome attachments and for cytokinesis. We here demonstrate that a protein arginine methyltransferase PRMT1, which are overexpressed in various types of cancer including lung and bladder cancer, methylates arginine 887 in an Aurora Kinase B (AURKB)-binding region of INCENP both in vitro and in vivo. R887-substituted INCENP revealed lower binding-affinity to AURKB than wild-type INCENP in the presence of PRMT1. Knockdown of PRMT1 as well as overexpression of methylation-inactive INCENP attenuated the AURKB activity in cancer cells, and resulted in abnormal chromosomal alignment and segregation. Furthermore, introduction of methylation-inactive INCENP into cancer cells reduced the growth rate, compared with those introduced wild-type INCENP or Mock. Our data unveils a novel mechanism of PRMT1-mediated CPC regulation through methylation of INCENP.

Highlights

During mitosis, the chromosomal passenger complex (CPC) comprising inner centromere protein (INCENP), Aurora Kinase B (AURKB), Borealin/Dasra B and Survivin plays critical roles at the centromere in ensuring strict chromosome alignment and segregation [1, 2]
293T cells were co-transfected with a FLAG-INCENPWT vector or a FLAG-INCENP-R887A vector and an HA-Protein arginine methyltransferase 1 (PRMT1) vector, and western blot analysis was performed after immunoprcipitation of the INCENP protein (Figure 2C)
Since our data revealed that PRMT1-mediated INCENP methylation is critical for the activation of AURKB, we examined the effect of PRMT1 knockdown on the cell division of cancer cells

Summary

Introduction

The chromosomal passenger complex (CPC) comprising inner centromere protein (INCENP), Aurora Kinase B (AURKB), Borealin/Dasra B and Survivin plays critical roles at the centromere in ensuring strict chromosome alignment and segregation [1, 2]. The C-terminus of INCENP binds AURKB through its highly-conserved IN box and this binding is essential for triggering AURKB activation [9]. This interaction is shown to enable AURKB to phosphorylate a C-terminal TSS (threonine-serine-serine) motif in INCENP and threonine 232 in the T-loop of its kinase domain, which results in full activation of AURKB [10,11,12]. Other post-translational modifications including methylation on INCENP have not been characterized

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