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Gcn5 Functions in Mammalian Development
Author(s) -
Atanassov Boyko,
Hirsch Calley,
Dent Sharon
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.78.1
Subject(s) - biology , microbiology and biotechnology , proteasome , telomere , ubiquitin , shelterin , embryonic stem cell , induced pluripotent stem cell , genetics , transcription factor , gene , dna binding protein
We have created a series of mutations in the mouse Gcn5 gene in order to define the functions of this HAT in a mammalian system. Deletion of Gcn5 leads early embryonic death and to telomere dysfunction. Biochemical studies reveal that depletion of Gcn5 or ubiquitin specific protease 22 (Usp22), which is another bona fide component of the Gcn5‐containing SAGA‐type complex, increases the turnover of two shelterin proteins, TRF1 and POT1a. Inhibition of the proteasomes opposes this effect. The Usp22 deubiquitylating module requires association with SAGA complexes for activity, and we find that depletion of Gcn5 compromises this association in mammalian cells. Overall, these results indicate that Gcn5 regulates TRF1 levels through effects on Usp22 activity and SAGA integrity. These studies provide the first indication that Gcn5 and mammalian SAGA influence telomere maintenance and the first demonstration that SAGA affects protein stability. Current studies are directed at identifying additional USP22 targets. We have also created Gcn5 null ES cells. Upon removal of LIF, these cells lose pluripotency more quickly than do wild type ES cells. Preliminary data suggest that Gcn5 may be a key regulator of the master transcription factors required for maintenance of the pluripotent state.