PRMT6-mediated H3R2me2a guides Aurora B to chromosome arms for proper chromosome segregation

Seul Kim,Ki-Tae Hwang,Jee Won Hwang,Chang-Young Jang,Yong Kee Kim,Nam Hyun Kim,Nayeon Myung,Young A Kim,Ji Eun Park

doi:10.1038/s41467-020-14511-w

Abstract

The kinase Aurora B forms the chromosomal passenger complex (CPC) together with Borealin, INCENP, and Survivin to mediate chromosome condensation, the correction of erroneous spindle-kinetochore attachments, and cytokinesis. Phosphorylation of histone H3 Thr3 by Haspin kinase and of histone H2A Thr120 by Bub1 concentrates the CPC at the centromere. However, how the CPC is recruited to chromosome arms upon mitotic entry is unknown. Here, we show that asymmetric dimethylation at Arg2 on histone H3 (H3R2me2a) by protein arginine methyltransferase 6 (PRMT6) recruits the CPC to chromosome arms and facilitates histone H3S10 phosphorylation by Aurora B for chromosome condensation. Furthermore, in vitro assays show that Aurora B preferentially binds to the H3 peptide containing H3R2me2a and phosphorylates H3S10. Our findings indicate that the long-awaited key histone mark for CPC recruitment onto mitotic chromosomes is H3R2me2a, which is indispensable for maintaining appropriate CPC levels in dynamic translocation throughout mitosis.

Highlights

The kinase Aurora B forms the chromosomal passenger complex (CPC) together with Borealin, INCENP, and Survivin to mediate chromosome condensation, the correction of erroneous spindle-kinetochore attachments, and cytokinesis
The metaphase plate width was significantly increased in PRMT6depleted cells (Fig. 1c, Supplementary Fig. 1g), suggesting that protein arginine methyltransferase 6 (PRMT6) is involved in aspects of chromosome integrity such as chromosome condensation, chromosome alignment, and centromeric cohesion during mitosis
Because PRMT6 can act as a methyltransferase for mitotic regulators involved in fastidious mitotic processes, we investigated whether H3R2me2a is responsible for chromosome integrity

Summary

Introduction

The kinase Aurora B forms the chromosomal passenger complex (CPC) together with Borealin, INCENP, and Survivin to mediate chromosome condensation, the correction of erroneous spindle-kinetochore attachments, and cytokinesis. We show that asymmetric dimethylation at Arg[2] on histone H3 (H3R2me2a) by protein arginine methyltransferase 6 (PRMT6) recruits the CPC to chromosome arms and facilitates histone H3S10 phosphorylation by Aurora B for chromosome condensation. After achieving chromosome condensation via H3S10ph on chromosome arms in early stages of mitosis, CPCs are concentrated at centromeres by Haspin-mediated H3T3ph[14,15,16] and Bub1-mediated histone H2A Thr[120] phosphorylation (H2AT120ph)[16]. The removal of cohesin from chromosome arms by Aurora B/Cdk1-mediated sororin phosphorylation and concomitant recruitment of the cohesion release factor Wingsapart like protein (Wap1) contributes to centromeric enrichment of Haspin[20]. The sequential activation of mitotic kinases and phosphatases operates a methyl/phospho switch because H3S10ph dissociates heterochromatin protein 1 (HP1) from trimethylated Lys[9] in histone H3 (H3K9me3) and converts the HP1-mediated recruitment of the CPC to a mitotic mode of recruitment[22,23]

Methods

Results

Conclusion