Aurora-A mediated histone H3 phosphorylation of threonine 118 controls condensin I and cohesin occupancy in mitosis.

Candice L Wike,Reva Hawkins,Damien F Hudson,Michelle B Ferdinand,Zhihong Chen,Michael G Poirier,Tao Zhang,Jill Schumacher,Hillary K Graves,Matthew D Gibson,Jennifer J Ottesen,Jessica K Tyler

doi:10.7554/elife.11402

Abstract

Phosphorylation of histone H3 threonine 118 (H3 T118ph) weakens histone DNA-contacts, disrupting the nucleosome structure. We show that Aurora-A mediated H3 T118ph occurs at pericentromeres and chromosome arms during prophase and is lost upon chromosome alignment. Expression of H3 T118E or H3 T118I (a SIN mutation that bypasses the need for the ATP-dependent nucleosome remodeler SWI/SNF) leads to mitotic problems including defects in spindle attachment, delayed cytokinesis, reduced chromatin packaging, cohesion loss, cohesin and condensin I loss in human cells. In agreement, overexpression of Aurora-A leads to increased H3 T118ph levels, causing cohesion loss, and reduced levels of cohesin and condensin I on chromatin. Normal levels of H3 T118ph are important because it is required for development in fruit flies. We propose that H3 T118ph alters the chromatin structure during specific phases of mitosis to promote timely condensin I and cohesin disassociation, which is essential for effective chromosome segregation.

Highlights

The packaging of the eukaryotic genome into chromatin facilitates the temporal and spatial regulation of all genomic activities, including DNA repair, replication, transcription and mitosis
Given that the H3 T118 for isoleucine (T118I) mutant or overexpression of Aurora-A led to premature release of cohesin and condensin I from chromosomes, we propose that H3 T118ph alters chromosome structure during mitosis to help dissociate cohesion and condensin I
H3 T118ph is dynamically regulated through mitosis by the Aurora-A kinase, occurring at pericentromeric regions and at discrete locations on chromosome arms

Summary

Introduction

The packaging of the eukaryotic genome into chromatin facilitates the temporal and spatial regulation of all genomic activities, including DNA repair, replication, transcription and mitosis. Chromatin comprises arrays of nucleosomes, where each nucleosome has ~146 base pairs of DNA wrapped 1.75 times around a histone octamer composed of two molecules each of core histone H3, H4, H2A, and H2B (Kornberg, 1974). Repetitive arrays of nucleosomes are further compacted by higherorder folding, requiring additional proteins including linker histones. One important means by which the cell achieves accurate regulation of genomic processes, including mitosis, is via post-translational modifications (PTMs) of the core histones (Strahl and Allis, 2000). The PTMs, usually occurring on the N- and C-terminal tails of the histones, generally serve to recruit reader proteins to the chromatin. PTMs occur on the histone globular domains, but are

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