The role and regulation of histone H2B monoubiquitination during tumorigenesis

by Theresa Gorsler
Doctoral thesis
Date of Examination:2013-06-03
Date of issue:2014-05-23
Advisor:Prof. Dr. Steven Johnsen
Referee:Prof. Dr. Steven Johnsen
Referee:Prof. Dr. Holger Reichardt
Referee:Prof. Dr. Dieter Kube
Persistent Address: http://dx.doi.org/10.53846/goediss-4504

 

 

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Abstract

English

Posttranslational histone modifications are recognized as important regulators of gene expression. One of them, the monoubiquitination of lysine 120 of histone H2B (H2Bub1), has diverse functions and is involved in gene transcription as well as in controlling mRNA processing, DNA repair and DNA replication. Notably, H2Bub1 is associated with actively transcribed genes and has been linked to ongoing transcription. The misregulation of H2Bub1-modifying machinery has been observed to be tightly linked with different types of cancer. In the course of this study we clarified aspects of the regulation of the H2B ubiquitinating enzymes and presented data which support the hypothesis that the RNF20/RNF40 complex has a tumor-suppressor function probably through its regulation of H2Bub1. Moreover, we present data that demonstrate a rapid and massive loss of H2Bub1 following various cell stresses. Elucidating the mechanism and signaling pathways which control this process was one major goal of this study. It was demonstrated that H2Bub1 depletion could be rescued through knockdown of various subunits of the deubiquitinating module of the SAGA complex. ChIP-seq analyses obtained in this study demonstrated that H2Bub1 does not cover the entire transcribed region uniformly nor do the average ChIP signal profiles of H2Bub1 correlate with gene expression. However, the deubiquitination and therefore probably the new ubiquitination do correlate with gene activity. Collectively, these studies have uncovered important mechanisms regulating H2Bub1 and may serve as a basis for developing a more solid knowledge of stress-induced H2B deubiquitination and the role of H2B monoubiquitination during tumorigenesis and metastasis. The data provide a potential role of H2Bub1 in epigenetic-based therapy for cancer.
Keywords: tumorigenesis; histone H2B monoubiquitination; transcription
 
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