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      Emerging roles of the CIP2A–TopBP1 complex in genome integrity

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      NAR Cancer
      Oxford University Press

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          Abstract

          CIP2A is an inhibitor of the tumour suppressor protein phosphatase 2A. Recently, CIP2A was identified as a synthetic lethal interactor of BRCA1 and BRCA2 and a driver of basal-like breast cancers. In addition, a joint role of TopBP1 (topoisomerase IIβ-binding protein 1) and CIP2A for maintaining genome integrity during mitosis was discovered. TopBP1 has multiple functions as it is a scaffold for proteins involved in DNA replication, transcriptional regulation, cell cycle regulation and DNA repair. Here, we briefly review details of the CIP2A–TopBP1 interaction, its role in maintaining genome integrity, its involvement in cancer and its potential as a therapeutic target.

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          Most cited references45

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          ColabFold: making protein folding accessible to all

          ColabFold offers accelerated prediction of protein structures and complexes by combining the fast homology search of MMseqs2 with AlphaFold2 or RoseTTAFold. ColabFold’s 40−60-fold faster search and optimized model utilization enables prediction of close to 1,000 structures per day on a server with one graphics processing unit. Coupled with Google Colaboratory, ColabFold becomes a free and accessible platform for protein folding. ColabFold is open-source software available at https://github.com/sokrypton/ColabFold and its novel environmental databases are available at https://colabfold.mmseqs.com . ColabFold is a free and accessible platform for protein folding that provides accelerated prediction of protein structures and complexes using AlphaFold2 or RoseTTAFold.
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            Phosphatase: PP2A structural importance, regulation and its aberrant expression in cancer.

            Protein Phosphatase 2A (PP2A) is an important and ubiquitously expressed serine threonine phosphatase and regulates the function by dephosphorylating many critical cellular molecules like Akt, p53, c-Myc and β-catenin. It plays a critical role in cellular processes, such as cell proliferation, signal transduction and apoptosis. Structurally, it is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity. PP2A undergoes post-translational modifications (i.e. phosphorylation and methylation), which in turn, regulates its enzymatic activity. Aberrant expression, mutations and somatic alterations of the PP2A scaffold and regulatory subunits have been observed in various human malignancies, including lung, breast, skin and colon cancer, highlighting its role as a 'tumor suppressor'. This review is focused on the structural complexity of serine/threonine phosphatase PP2A and summarizes its expression pattern in cancer. Additionally, the PP2A interacting and regulatory proteins and substrates are also discussed. Finally, the mouse models developed to understand the biological role of PP2A subunits in an in vivo model system are also reviewed in this article. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
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              Cancerous inhibitor of protein phosphatase 2A, an emerging human oncoprotein and a potential cancer therapy target.

              Protein phosphatase 2A (PP2A) complexes function as tumor suppressors by inhibiting the activity of several critical oncogenic signaling pathways. Consequently, inhibition of the PP2A phosphatase activity is one of many prerequisites for the transformation of normal human cells into cancerous cells. However, mechanisms for PP2A inactivation in human cancers are poorly understood. The aberrant expression of cancerous inhibitor of protein phosphatase 2A (CIP2A), a recently identified endogenous PP2A inhibitor in malignant cells, is one such mechanism. Various independent studies have validated CIP2A's role in promoting tumor growth and resistance to apoptosis and senescence-inducing therapies. Notably, high CIP2A expression predicts poor patient prognosis in several human cancer types. Among the oncogenic proteins dephosphorylated by PP2A, the MYC oncoprotein, which is phosphorylated at serine 62, has surfaced as a marker for the oncogenic activity of CIP2A. The positive-feedback loop between CIP2A and MYC augments the activity of MYC in cancer cells. In addition, CIP2A promotes the phosphorylation and activity of additional oncoproteins, including E2F1 and AKT. However, CIP2A is not essential for normal mouse growth and development. These findings indicate that CIP2A is a novel anticancer target based on PP2A reactivation and inhibition of the oncogenic activity of its downstream effectors. The potential approaches and feasibility of targeting CIP2A are discussed here. ©2013 AACR
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                Author and article information

                Contributors
                Journal
                NAR Cancer
                NAR Cancer
                narcancer
                NAR Cancer
                Oxford University Press
                2632-8674
                December 2023
                11 October 2023
                11 October 2023
                : 5
                : 4
                : zcad052
                Affiliations
                Department of Biology, University of Copenhagen , Copenhagen 2200, Denmark
                Department of Biology, University of Copenhagen , Copenhagen 2200, Denmark
                Department of Biology, University of Copenhagen , Copenhagen 2200, Denmark
                Department of Biology, University of Copenhagen , Copenhagen 2200, Denmark
                Author notes
                To whom correspondence should be addressed. Tel: +45 35330444; Email: vibe@ 123456bio.ku.dk
                Correspondence may also be addressed to Henning Ummethum. Tel: +45 35330444; Email: henning.ummethum@ 123456bio.ku.dk
                Author information
                https://orcid.org/0000-0002-4830-5247
                https://orcid.org/0000-0002-1633-0560
                Article
                zcad052
                10.1093/narcan/zcad052
                10566317
                37829116
                380b6b30-e38a-46fa-9efd-3bd5ffe5cec4
                © The Author(s) 2023. Published by Oxford University Press on behalf of NAR Cancer.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License ( https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@ 123456oup.com

                History
                : 24 September 2023
                : 27 August 2023
                : 15 July 2023
                Page count
                Pages: 6
                Funding
                Funded by: The Danish Cancer Society, DOI 10.13039/100008363;
                Award ID: R325-A18939
                Funded by: Fabrikant Einar Willumsens Mindelegat, DOI 10.13039/501100010347;
                Funded by: Dagmar Marshalls Foundation, DOI 10.13039/100007403;
                Funded by: Novo Nordisk Foundation, DOI 10.13039/501100009708;
                Categories
                AcademicSubjects/SCI00030
                AcademicSubjects/SCI00980
                AcademicSubjects/SCI01060
                AcademicSubjects/SCI01140
                AcademicSubjects/SCI01180
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