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      Increased expression of BubR1 protects against aneuploidy and cancer and extends healthy lifespan

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          Abstract

          The BubR1 gene encodes for a mitotic regulator that ensures accurate segregation of chromosomes through its role in the mitotic checkpoint and the establishment of proper microtubule-kinetochore attachments. Germline mutations that reduce BubR1 abundance cause aneuploidy, shorten lifespan, and induce premature aging phenotypes and cancer in both humans and mice. Reduced BubR1 expression is also a feature of chronological aging, but whether this age-related decline has biological consequences is unknown. Using a transgenic approach in mice, we show that sustained high expression of BubR1 preserves genomic integrity and reduces tumorigenesis, even in the presence of genetic alterations that strongly promote aneuplodization and cancer, such as oncogenic Ras. We find that BubR1 overabundance exerts its protective effect by correcting mitotic checkpoint impairment and microtubule-kinetochore attachment defects. Furthermore, sustained high expression of BubR1 extends lifespan and delays age-related deterioration and aneuploidy in several tissues. Collectively, these data uncover a generalized function for BubR1 in counteracting defects that cause whole chromosome instability and suggest that modulating BubR1 provides a unique opportunity to extend healthy lifespan.

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          Most cited references47

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          Boveri revisited: chromosomal instability, aneuploidy and tumorigenesis.

          The mitotic checkpoint is a major cell cycle control mechanism that guards against chromosome missegregation and the subsequent production of aneuploid daughter cells. Most cancer cells are aneuploid and frequently missegregate chromosomes during mitosis. Indeed, aneuploidy is a common characteristic of tumours, and, for over 100 years, it has been proposed to drive tumour progression. However, recent evidence has revealed that although aneuploidy can increase the potential for cellular transformation, it also acts to antagonize tumorigenesis in certain genetic contexts. A clearer understanding of the tumour suppressive function of aneuploidy might reveal new avenues for anticancer therapy.
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            53BP1 nuclear bodies form around DNA lesions generated by mitotic transmission of chromosomes under replication stress.

            Completion of genome duplication is challenged by structural and topological barriers that impede progression of replication forks. Although this can seriously undermine genome integrity, the fate of DNA with unresolved replication intermediates is not known. Here, we show that mild replication stress increases the frequency of chromosomal lesions that are transmitted to daughter cells. Throughout G1, these lesions are sequestered in nuclear compartments marked by p53-binding protein 1 (53BP1) and other chromatin-associated genome caretakers. We show that the number of such 53BP1 nuclear bodies increases after genetic ablation of BLM, a DNA helicase associated with dissolution of entangled DNA. Conversely, 53BP1 nuclear bodies are partially suppressed by knocking down SMC2, a condensin subunit required for mechanical stability of mitotic chromosomes. Finally, we provide evidence that 53BP1 nuclear bodies shield chromosomal fragile sites sequestered in these compartments against erosion. Together, these data indicate that restoration of DNA or chromatin integrity at loci prone to replication problems requires mitotic transmission to the next cell generations. © 2011 Macmillan Publishers Limited. All rights reserved.
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              Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction.

              Potential repair by cell grafting or mobilizing endogenous cells holds particular attraction in heart disease, where the meager capacity for cardiomyocyte proliferation likely contributes to the irreversibility of heart failure. Whether cardiac progenitors exist in adult myocardium itself is unanswered, as is the question whether undifferentiated cardiac precursor cells merely fuse with preexisting myocytes. Here we report the existence of adult heart-derived cardiac progenitor cells expressing stem cell antigen-1. Initially, the cells express neither cardiac structural genes nor Nkx2.5 but differentiate in vitro in response to 5'-azacytidine, in part depending on Bmpr1a, a receptor for bone morphogenetic proteins. Given intravenously after ischemia/reperfusion, cardiac stem cell antigen 1 cells home to injured myocardium. By using a Cre/Lox donor/recipient pair (alphaMHC-Cre/R26R), differentiation was shown to occur roughly equally, with and without fusion to host cells.
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                Author and article information

                Journal
                100890575
                21417
                Nat Cell Biol
                Nat. Cell Biol.
                Nature cell biology
                1465-7392
                1476-4679
                7 June 2013
                16 December 2012
                January 2013
                10 July 2013
                : 15
                : 1
                : 96-102
                Affiliations
                [1 ]Department of Pediatric and Adolescent Medicine, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA
                [2 ]Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA
                [3 ]Department of Medicine, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA
                [4 ]Department of Immunology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA
                [5 ]Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, 9700 RB, The Netherlands
                Author notes
                [§]

                Shared first authors

                [* ]Corresponding author: Jan M. van Deursen, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, Tel: 507-284-2524, vandeursen.jan@ 123456mayo.edu
                Article
                NIHMS419698
                10.1038/ncb2643
                3707109
                23242215
                e18809eb-9532-4ea5-b076-fed1024cb23b

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                History
                Funding
                Funded by: National Cancer Institute : NCI
                Award ID: R01 CA096985 || CA
                Categories
                Article

                Cell biology
                Cell biology

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