dRYBP transcription-dependent and transcription-independent functions in Drosophila development
Author
Fereres Rapoport, SolAdvisor
Busturia Jimeno, Ana deEntity
UAM. Departamento de Biología Molecular; Centro de Biología Molecular Severo Ochoa (CBM)Date
2014-05-30Subjects
Drosophilas - 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: 30-05-2014Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Abstract
In this Thesis we have analyzed, using Drosophila as a model system, the function of dRYBP
(drsosophila Ring and YY1 binding protein) in the control of gene expression. The genetic and
biochemical analysis of dRYBP reveals its role in the epigenetic control of gene expression and
in the regulation of cell death. dRYBP controls these processes by two different mechanisms:
one, a transcription-dependent mechanism whereby dRYBP, together with the Polycomb and
trithorax proteins, modulates levels of post-translationally modified histones. The second one, a
transcription-independent mechanism whereby dRYBP regulates the apoptotic pathway through
its interaction with the SCF E3 ubiquitin ligase complex, involved in proteasomal degradation
of target proteins. The conclusions of this Thesis are: 1) The dRYBP protein coexists, in
Drosophila S2 cells, in two different forms: the dRYBP and the monoubiquitylated dRYBP
(dRYBPub) proteins. Moreover, the dRYBP protein binds to ubiquitylated proteins through its
N-terminal, where the NZF domain is located. 2) The dRYBP protein interacts with the H2A,
H2B, H2Aub and H2Bub histones in Drosophila S2 cells. Additionally, dRYBP genetically
interacts with Sce/dRing, dkdm2 and dBre1 and biochemically, in Drosophila wild type
embryonic nuclear protein extracts (dNE), with SCE/dRING, dKDM2 and dBRE1. 3) The
dRYBP protein does not biochemically interact with the PSC, PC, PH and EZ proteins and
dBRE1 does not interact with the SCE/dRING, dKDM2 and EZ proteins in dNE. 4) Inactivation
of dRYBP decreases levels of monoubiquitylated H2A (H2Aub) and monomethylated H3K4
(H3K4me). 5) dRYBP counteracts dKDM2-mediated H3K36me2
demethylation and dBRE1-
mediated H2B monoubiqutylation. These dRYBP-mediated activities may therefore attenuate
dkdm2-mediated repression and dBRE1-mediated activation. 6) The dRYBP gene interacts
genetically with skpA, dCul1 and slmb, all members of the SCF E3 ubiquitin ligase complex.
Moreover, the dRYBP protein biochemically interacts with SKPA and dCUL1 proteins. 7)
Inactivation of dRYBP, skpA, dCul1 and slmb induces apoptosis in the wing imaginal disc and
the inactivation of skpA- and dRYBP-induced apoptosis is dependent on the expression levels of
the pro-apoptotic gene rpr and the anti-apoptotic protein DIAP1. Thus the dRYBP-SCF
complex functions by inhibiting the intrinsic apoptotic pathway. 8) Inactivation of skpA in wing
imaginal discs and in Drosophila S2 cells, induces the transcriptional activation of rpr and
diap1, increases Rpr protein levels and decreases DIAP1 protein levels. 9) High levels of SKPA
rescues the apoptotic wing phenotype induced by overexpression of Rpr. Moreover, in human
HEK293 cells, SKPA protein biochemically interacts with Rpr and DIAP1 proteins and SKPA
overexpression decreases Rpr protein levels, suggesting that the dRYBP-SCF complex posttranslationally
regulates Rpr protein levels. 10) High levels of SKPA inhibit both the apoptosis
that occurs during normal leg development and X-ray-induced apoptosis
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