Gcn5 and SAGA regulate shelterin protein turnover and telomere maintenance.
Histone acetyltransferases (HATs) play important roles in gene regulation and DNA repair by influencing the accessibility of chromatin to transcription factors and repair proteins. Here, we show that deletion of Gcn5 leads to telomere dysfunction in mouse and human cells. Biochemical studies reveal that depletion of Gcn5 or ubiquitin-specific protease 22 (Usp22), which is another bona fide component of the Gcn5-containing SAGA complex, increases ubiquitination and turnover of TRF1, a primary component of the telomeric shelterin complex. Inhibition of the proteasome or overexpression of USP22 opposes this effect. The USP22 deubiquitinating module requires association with SAGA complexes for activity, and we find that depletion of Gcn5 compromises this association in mammalian cells. Thus, our results indicate that Gcn5 regulates TRF1 levels through effects on Usp22 activity and SAGA integrity.
Atanassov
Boyko S
BS
Department of Biochemistry and Molecular Biology, University of Texas M.D. Anderson Cancer Center, Houston, 77030, USA.
Evrard
Yvonne A
YA
Multani
Asha S
AS
Zhang
Zhijing
Z
Tora
László
L
Devys
Didier
D
Chang
Sandy
S
Dent
Sharon Y R
SY
D000818:Animals; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000235:genetics; D017353:Gene Deletion; D006801:Humans; D051379:Mice; D008954:Models, Biological; D061988:Proteasome Inhibitors; D055550:Protein Stability; D000089804:Shelterin Complex; D016615:Telomere / Q000378:metabolism*; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D035321:Telomeric Repeat Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D013869:Thiolester Hydrolases / Q000235:genetics / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000099224:p300-CBP-Associated Factor
D061988:Proteasome Inhibitors; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; D035321:Telomeric Repeat Binding Protein 1; D013869:Thiolester Hydrolases; D043222:Ubiquitin Thiolesterase; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C440849:POT1 protein, human; C527170:Usp22 protein, human
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