Exploring the roles of the SMC5/6 complex in cancer, ageing and kidney disorders
Author
Schiavoni, FedericaAdvisor
Fernandez Capetillo, OscarEntity
UAM. Departamento de Biología Molecular; Centro Nacional de Investigaciones Oncológicas (CNIO)Date
2017-06-02Subjects
Oncogenes - Tesis doctorales; Enfermedades neurodegenerativas - Aspectos genéticos - Tesis doctorales; Riñones - Enfermedades - Aspectos genéticos - Tesis doctorales; Biología y Biomedicina / BiologíaNote
Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 02-06-2017Esta tesis tiene embargado el acceso al texto completo hasta el 02-12-2018
Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Abstract
The SMC5/6 complex is part of the Structural Maintenance of Chromosomes (SMC) family of proteins, which includes condensin and cohesin and whose main function is the regulation of chromosomal architecture and organization. While it is known that SMC5/6 participates in genome maintenance, how and where the complex operates remains unclear. With the use of mouse models our work has revealed that NSMCE2, a SUMO ligase that is an integral member of the SMC5/6 complex, suppresses cancer and ageing in mice independently of its SUMO ligase activity. At the cellular level, NSMCE2 deficiency leads to severe segregation defects and increased recombination rates, which would be consistent with a role of the SMC5/6 complex in the resolution of joint DNA molecules before chromosome segregation. Besides the overall accelerated ageing that occurs when Nsmce2 is deleted in adult animals, we here show that these mice present a distinct phenotype on their kidneys that presents all the hallmarks of Karyomegalic interstitial nephritis (KIN). KIN is a progressive kidney disease that in humans has been linked either to exposure to Ochratoxin A, a Topoisomerase II (TOPOII) inhibitor, or to inherit mutations in FAN1, an endonuclease mainly associated to the repair of interstrand cross-links (ICL). Our data suggests that NSMCE2 deficiency leads to the accumulation of topological problems, which would ultimately lead to polyploidy and be the cause of the karyomegaly. In support of this, NSMCE2 deficiency sensitizes cells to the inhibition of TOPOII, and leads to a number of phenotypes that are observed upon TOPOII inhibition. In summary, we here present the second mutation that can trigger KIN in mammals, and propose that topological problems, rather than deficiencies in ICLs repair, are the actual cause of this disease.
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