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Mass Spectrometry Analysis to Identify Ubiquitylation of EYFP-tagged CENP-A EYFP-CENP-A
Published on: June 10, 2020
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CENP-A Ubiquitylation Is Inherited through Dimerization between Cell Divisions.
Yohei Niikura1, Risa Kitagawa1, Katsumi Kitagawa2
1Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USA.
Cell Reports
|April 8, 2016
Summary
Centromere location is determined by CENP-A ubiquitylation, which is inherited between cell divisions through CENP-A dimerization. This epigenetic mark ensures accurate centromere inheritance and prevents neocentromere formation.
Area of Science:
- Epigenetics and Chromatin Biology
- Molecular Cell Biology
- Genetics and Genomics
Background:
- Centromere identity is epigenetically determined by the histone H3 variant CENP-A, independent of DNA sequence.
- The mechanism of centromere inheritance, ensuring faithful transmission of CENP-A to daughter cells, remains largely unelucidated.
- Previous work identified CENP-A K124 ubiquitylation by the CUL4A-RBX1-COPS8 E3 ligase as crucial for CENP-A centromeric deposition.
Purpose of the Study:
- To investigate the mechanism of centromere inheritance and the role of CENP-A ubiquitylation in this process.
- To determine if CENP-A ubiquitylation is inherited across cell divisions and if it is essential for recruiting new CENP-A.
- To explore the structural requirements, specifically CENP-A dimerization, for the inheritance of CENP-A ubiquitylation.
Main Methods:
- In vivo and in vitro experiments utilizing dimerization mutants and fusion mutants of CENP-A.
- Analysis of CENP-A ubiquitylation status across cell divisions.
- Investigation of CENP-A recruitment to centromeres in the presence of ubiquitylated CENP-A.
- Overexpression studies of monoubiquitin-fused CENP-A mutants to assess neocentromere formation.
Main Results:
- Pre-existing ubiquitylated CENP-A is essential for the recruitment of newly synthesized CENP-A to the centromere.
- CENP-A ubiquitylation is demonstrably inherited between successive cell divisions.
- CENP-A dimerization is a critical requirement for the inheritance of its ubiquitylation status.
- Overexpression of a monoubiquitin-fused CENP-A mutant leads to the formation of neocentromeres at ectopic chromosomal locations.
Conclusions:
- CENP-A ubiquitylation acts as an inherited epigenetic mark that dictates centromere location.
- CENP-A dimerization is essential for the propagation of this ubiquitylation mark, thereby ensuring centromere inheritance.
- The findings support a model where inherited CENP-A ubiquitylation, mediated by dimerization, defines centromere identity and prevents aberrant neocentromere formation.
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