Resetting a functional G1 nucleus after mitosis

© The Author(s) 2015. The maintenance of the correct cellular information goes beyond the simple transmission of an intact genetic code from one generation to the next. Epigenetic changes, topological cues and correct protein-protein interactions need to be re-established after each cell division to allow the next cell cycle to resume in the correct regulated manner. This process begins with mitotic exit and re-sets all the changes that occurred during mitosis thus restoring a functional G1 nucleus in preparation for the next cell cycle. Mitotic exit is triggered by inactivation of mitotic kinases and the reversal of their phosphorylation activities on many cellular components, from nuclear lamina to transcription factors and chromatin itself. To reverse all these phosphorylations, phosphatases act during mitotic exit in a timely and spatially controlled manner directing the events that lead to a functional G1 nucleus. In this review, we will summarise the recent developments on the control of phosphatases and their known substrates during mitotic exit, and the key steps that control the restoration of chromatin status, nuclear envelope reassembly and nuclear body re-organisation. Although pivotal work has been conducted in this area in yeast, due to differences between the mitotic exit network between yeast and vertebrates, we will mainly concentrate on the vertebrate system.BBSRC grant (BB/K017632/1)

Repo-Man-PP1:A link between chromatin remodelling and nuclear envelope reassembly

Coordination of late mitotic events is crucial for the maintenance of genome stability and for the control of gene expression after cell division. Reversible protein phosphorylation regulates this process by de-phosphorylation of mitotic phospho-proteins in a sequential and coordinated manner: this allows an orderly sequence of events to take place during mitotic exit. We have identified Repo-Man/PP1 as a phosphatase complex that regulates temporally and spatially chromatin re-organization and nuclear envelope re-formation during anaphase-telophase

Contribution of histone variants to aneuploidy: a cancer perspective

Data availability statement: The original contributions presented in the study are included in the article's Supplementary Material, available online at: https://www.frontiersin.org/articles/10.3389/fgene.2023.1290903/full#supplementary-material, further inquiries can be directed to the corresponding authors.Copyright © 2023 Ragusa and Vagnarelli. Histone variants, which generally differ in few amino acid residues, can replace core histones (H1, H2A, H2B, and H3) to confer specific structural and functional features to regulate cellular functions. In addition to their role in DNA packaging, histones modulate key processes such as gene expression regulation and chromosome segregation, which are frequently dysregulated in cancer cells. During the years, histones variants have gained significant attention as gatekeepers of chromosome stability, raising interest in understanding how structural and functional alterations can contribute to tumourigenesis. Beside the well-established role of the histone H3 variant CENP-A in centromere specification and maintenance, a growing body of literature has described mutations, aberrant expression patterns and post-translational modifications of a variety of histone variants in several cancers, also coining the term “oncohistones.” At the molecular level, mechanistic studies have been dissecting the biological mechanisms behind histones and missegregation events, with the potential to uncover novel clinically-relevant targets. In this review, we focus on the current understanding and highlight knowledge gaps of the contribution of histone variants to aneuploidy, and we have compiled a database (HistoPloidyDB) of histone gene alterations linked to aneuploidy in cancers of the The Cancer Genome Atlas project.BBSRC grant BB/V013920/1 to PV

Back to the new beginning: Mitotic exit in space and time

The ultimate goal of cell division is to generate two identical daughter cells that resemble the mother cell from which they derived. Once all the proper attachments to the spindle have occurred, the chromosomes have aligned at the metaphase plate and the spindle assembly checkpoint (a surveillance mechanism that halts cells form progressing in the cell cycle in case of spindle – microtubule attachment errors) has been satisfied, mitotic exit will occur. Mitotic exit has the purpose of completing the separation of the genomic material but also to rebuild the cellular structures necessary for the new cell cycle. This stage of mitosis received little attention until a decade ago, therefore our knowledge is much patchier than the molecular details we now have for the early stages of mitosis. However, it is emerging that mitotic exit is not just the simple reverse of mitotic entry and it is highly regulated in space and time. In this review I will discuss the main advances in the field that provided us with a better understanding on the key role of protein phosphorylation/de-phosphorylation in this transition together with the concept of their spatial regulation. As this field is much younger, I will highlight general consensus, contrasting views together with the outstanding questions awaiting for answers

Chromosome Clustering in mitosis by the nuclear protein Ki-67

© 2021 The Author(s). Ki-67 is highly expressed in proliferating cells, a characteristic that made the protein a very important proliferation marker widely used in the clinic. However, the molecular functions and properties of Ki-67 remained quite obscure for a long time. Only recently important discoveries have shed some light on its function and shown that Ki-67 has a major role in the formation of mitotic chromosome periphery compartment, it is associated with protein phosphatase one (PP1) and regulates chromatin function in interphase and mitosis. In this review, we discuss the role of Ki-67 during cell division. Specifically, we focus on the importance of Ki-67 in chromosome individualisation at mitotic entry (prometaphase) and its contribution to chromosome clustering and nuclear remodelling during mitotic exit.Wellcome Trust. Investigator award 210742/Z/18/Z (Chromatin Re-Organisation at the Transition from Mitosis to G1: How Phospho-Switches Regulate the Process in Space and Time); Brunel University London (CHMLS scholarship)

Protein Phosphatases in chromatin structure and function

© 2018 The Author(s). Chromatin structure and dynamics are highly controlled and regulated processes that play an essential role in many aspects of cell biology. The chromatin transition stages and the factors that control this process are regulated by post-translation modifications, including phosphorylation. While the role of protein kinases in chromatin dynamics has been quite well studied, the nature and regulation of the counteracting phosphatases represent an emerging field but are still at their infancy. In this review we summarize the current literature on phosphatases involved in the regulation of chromatin structure and dynamics, with emphases on the major knowledge gaps that should require attention and more investigation.BBSC, The Wellcome Trust, Brunel Idea Award, Isambard scholarshi

How HP1 post-translational modifications regulate heterochromatin formation and maintenance

Copyright © 2020 by the authors. Heterochromatin Protein 1 (HP1) is a highly conserved protein that has been used as a classic marker for heterochromatin. HP1 binds to di- and tri-methylated histone H3K9 and regulates heterochromatin formation, functions and structure. Besides the well-established phosphorylation of histone H3 Ser10 that has been shown to modulate HP1 binding to chromatin, several studies have recently highlighted the importance of HP1 post-translational modifications and additional epigenetic features for the modulation of HP1-chromatin binding ability and heterochromatin formation. In this review, we summarize the recent literature of HP1 post-translational modifications that have contributed to understand how heterochromatin is formed, regulated and maintained.Wellcome Trust Investigator awar

The Role of Phosphatases in Nuclear Envelope Disassembly and Reassembly and Their Relevance to Pathologies

The role of kinases in the regulation of cell cycle transitions is very well established, however, over the past decade, studies have identified the ever-growing importance of phosphatases in these processes. It is well-known that an intact or otherwise non-deformed nuclear envelope (NE) is essential for maintaining healthy cells and any deviation from this can result in pathological conditions. This review aims at assessing the current understanding of how phosphatases contribute to the remodelling of the nuclear envelope during its disassembling and reformation after cell division and how errors in this process may lead to the development of diseases.The Wellcome Trus