Regulación y función de la endonucleasa específica de estructura Mus81-Mms4/EME1
Author
Gallo Fernández, MaríaAdvisor
Tercero Orduña, José AntonioEntity
UAM. Departamento de Biología MolecularDate
2017-09-18Subjects
ADN - Reparación - Tesis doctorales; Saccharomyces cerevisiae - 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: 18-09-2017Esta tesis tiene embargado el acceso al texto completo hasta el 18-03-2019
Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Abstract
The maintenance of genome stability during eukaryotic chromosome replication
and the fidelity of DNA synthesis are essential for cell survival and to prevent
pathological conditions that in metazoans could lead to cancer and other diseases.
Together with many other proteins, different specific endonucleases contribute to
genomic stability thanks to their ability to cleave DNA secondary structures that arise
during replication-associated repair processes or during replication restart after fork
blocks. In this PhD thesis, we focused our work on the study of one of these
endonucleases: the conserved heterodimeric complex Mus81-Mms4/EME1. This
endonuclease is composed of a catalytic subunit, Mus81/MUS81, and a non-catalytic
subunit, EME1/Mms4 (EME1/Eme1 in mammals, Schizosaccharomyces pombe and
plants, Mms4 in Saccharomyces cerevisiae and Drosophila), both of which are
required for the activity of the complex.
In this PhD thesis, using the budding yeast S. cerevisiae as a model organism,
we have studied the function and regulation of Mus81-Mms4 in proliferating cells. We
have found that this endonuclease is strictly regulated during the mitotic cell cycle by
Cdc28 (CDK)- and Cdc5 (PLK)- dependent phosphorylation of the non-catalytic subunit
Mms4. The phosphorylation of this subunit occurs only after bulk DNA synthesis and
before chromosome segregation, and is absolutely necessary for the endonuclease
function of the Mus81-Mms4 complex. Mus81-Mms4 regulation determines its activity
through the cell cycle, so that it is low during G1 and S phases and high at the G2/M
transition and during mitosis. Moreover, despite being required for dealing with DNA
lesions that hinder replication, Mus81-Mms4 activation is not induced by the presence
of DNA damage at replication forks. Full Mus81-Mms4 activity is only acquired when
cells finish S-phase and the endonuclease executes its function after the bulk of
genome replication is completed. The mode of regulation of Mus81-Mms4 restricts its
activity to a short period of the cell cycle, thus preventing its function during
chromosome replication and the potential negative consequences for genome stability
derived from its nucleolytic action. Yet, the controlled Mus81-Mms4 activity provides a
fail-safe mechanism that guarantees the resolution of DNA intermediates that may
remain after replication and require processing before chromosome segregation.
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