A noncatalytic function of the topoisomerase II CTD in Aurora B recruitment to inner centromeres during mitosis

Edgerton, Heather; Johansson, Marnie; Keifenheim, Daniel; Mukherjee, Soumya; Chacón, Jeremy M.; Bachant, Jeff; Gardner, Melissa K.; Clarke, Duncan J.

doi:10.1083/jcb.201511080

Cited by 43 publications

(63 citation statements)

References 64 publications

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“…One highly conserved SUMO substrate is Topoisomerase II (or Top2) (Clarke and Azuma, 2017). Sumoylation of Top2 C-terminal non-catalytic region leads to centromeric recruitment of Top2 itself to decatenate intertwined DNA before anaphase, as well as other mitotic factors (Claspin, Haspin and Aurora B kinases) to promote centromeric segregation (Azuma et al, 2003; Bachant et al, 2002; Dawlaty et al, 2008; Edgerton et al, 2016; Ryu et al, 2010; Ryu et al, 2015a). The SUMO pathway also affects centromeric histones and other mitotic regulators (Mukhopadhyay and Dasso, 2017).…”

Section: Sumo Modulates Chromosome Structures and Functionsmentioning

confidence: 99%

SUMO-Mediated Regulation of Nuclear Functions and Signaling Processes

2018

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Summary Since the discovery of SUMO twenty years ago, SUMO conjugation has become a widely-recognized post-translational modification that targets a myriad of proteins in many processes. Great progress has been made in understanding the SUMO pathway enzymes, substrate sumoylation, and the interplay between sumoylation and other regulatory mechanisms in a variety of contexts. As these research directions continue to generate insights into SUMO-based regulation, several mechanisms by which sumoylation and desumoylation can orchestrate large biological effects are emerging. These include the ability to target multiple proteins within the same cellular structure or process, respond dynamically to external and internal stimuli, and modulate signaling pathways involving other post-translational modifications. Focusing on nuclear function and intracellular signaling, this review highlights a broad spectrum of historical data and recent advances with the aim of providing an overview of mechanisms underlying SUMO-mediated global effects to stimulate further inquiry into intriguing roles of SUMO.

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Section: Sumo Modulates Chromosome Structures and Functionsmentioning

confidence: 99%

SUMO-Mediated Regulation of Nuclear Functions and Signaling Processes

2018

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“…See also Fig EV5. ª In Xenopus egg extracts and budding yeast (Edgerton et al, 2016;Yoshida et al, 2016), the CTD of TOP2A (Topo II in yeast) has been shown to interact with Haspin, the kinase responsible for histone H3 Thr-3 phosphorylation (H3pT3) in mitosis (Dai et al, 2005). Scale bars, 10 lm.…”

Section: Discussionmentioning

confidence: 99%

Histone H2A phosphorylation recruits topoisomerase II α to centromeres to safeguard genomic stability

et al. 2019

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Chromosome segregation in mitosis requires the removal of catenation between sister chromatids. Timely decatenation of sister DNAs at mitotic centromeres by topoisomerase IIa (TOP2A) is crucial to maintain genomic stability. The chromatin factors that recruit TOP2A to centromeres during mitosis remain unknown. Here, we show that histone H2A Thr-120 phosphorylation (H2ApT120), a modification generated by the mitotic kinase Bub1, is necessary and sufficient for the centromeric localization of TOP2A. Phosphorylation at residue-120 enhances histone H2A binding to TOP2A in vitro. The C-gate and the extreme C-terminal region are important for H2ApT120-dependent localization of TOP2A at centromeres. Preventing H2ApT120mediated accumulation of TOP2A at mitotic centromeres interferes with sister chromatid disjunction, as evidenced by increased frequency of anaphase ultra-fine bridges (UFBs) that contain catenated DNA. Tethering TOP2A to centromeres bypasses the requirement for H2ApT120 in suppressing anaphase UFBs. These results demonstrate that H2ApT120 acts as a landmark that recruits TOP2A to mitotic centromeres to decatenate sister DNAs. Our study reveals a fundamental role for histone phosphorylation in resolving centromere DNA entanglements and safeguarding genomic stability during mitosis.MZ designed and performed the majority of the experiments and analysis. CL designed and carried out the GST pulldown assays (Figs 3E and F, and 6L), the localization of TOP2A in HeLa and Sgo1-K492A cells (Fig 4C and D), the competitive localization of EGFP-TOP2A and Sgo1 (Fig 7A-D), as well as the deconvolution microscopy (Appendix Fig S4). HZ and SL helped express the GST-H2ApS120 protein. XY performed the experiments shown in Appendix Fig S1. QC, HY, JX, and JL provided technical assistance. WL provided reagents and constructive suggestions. FW conceived and supervised the project, designed the experiments, analyzed the data, and wrote the manuscript with the input from HY.

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“…Two recent studies in Xenopus and yeast showed that SUMOylated DNA topoisomerase IIα Cterminal domain can bind Haspin and regulate its localization at centromeres [34,35] (Figure 3). …”

Section: How Is Haspin Recruited Onto Chromosomes?mentioning

confidence: 99%

The Mitotic Protein Kinase Haspin and Its Inhibitors

Feizbakhsh¹,

Place²,

Fant³

et al. 2017

Protein Phosphorylation

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Haspin is an atypical serine/threonine protein kinase essential to mitosis. Unlike other protein kinases, its kinase domain does not require phosphorylation in order to be activated and bears very high substrate specificity and selectivity. Few substrates have been identified so far. Haspin phosphorylation on threonine 3 of Histone H3 from prophase to anaphase participates to centromeric Aurora B localization and ensures proper kinetochore-microtubule attachment. Haspin is also involved in the maintenance of centromeric cohesion and the mitotic spindle. Inhibitors have been developed and provided tools to dissect Haspin function. The kinase is now considered as a potential therapeutic target against cancer. We discuss here the latest findings on this essential mitotic protein.

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A noncatalytic function of the topoisomerase II CTD in Aurora B recruitment to inner centromeres during mitosis

Cited by 43 publications

References 64 publications

SUMO-Mediated Regulation of Nuclear Functions and Signaling Processes

SUMO-Mediated Regulation of Nuclear Functions and Signaling Processes

Histone H2A phosphorylation recruits topoisomerase II α to centromeres to safeguard genomic stability

The Mitotic Protein Kinase Haspin and Its Inhibitors

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