Functional characterization of RebL1 highlights the evolutionary conservation of oncogenic activities of the RBBP4/7 orthologue in Tetrahymena thermophila.
Amino Acid Sequence
Bacterial Proteins
/ metabolism
Biological Evolution
Conserved Sequence
DNA
/ metabolism
DNA-Binding Proteins
/ metabolism
Epigenesis, Genetic
Gene Expression
HEK293 Cells
Histone Chaperones
/ chemistry
Histones
/ metabolism
Humans
Neoplasms
/ metabolism
Oncogenes
Protozoan Proteins
/ chemistry
Retinoblastoma-Binding Protein 4
/ metabolism
Retinoblastoma-Binding Protein 7
/ metabolism
Tetrahymena thermophila
/ genetics
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
21 06 2021
21 06 2021
Historique:
accepted:
04
05
2021
revised:
22
04
2021
received:
29
03
2021
pubmed:
5
6
2021
medline:
15
7
2021
entrez:
4
6
2021
Statut:
ppublish
Résumé
Retinoblastoma-binding proteins 4 and 7 (RBBP4 and RBBP7) are two highly homologous human histone chaperones. They function in epigenetic regulation as subunits of multiple chromatin-related complexes and have been implicated in numerous cancers. Due to their overlapping functions, our understanding of RBBP4 and 7, particularly outside of Opisthokonts, has remained limited. Here, we report that in the ciliate protozoan Tetrahymena thermophila a single orthologue of human RBBP4 and 7 proteins, RebL1, physically interacts with histone H4 and functions in multiple epigenetic regulatory pathways. Functional proteomics identified conserved functional links for Tetrahymena RebL1 protein as well as human RBBP4 and 7. We found that putative subunits of multiple chromatin-related complexes including CAF1, Hat1, Rpd3, and MuvB, co-purified with RebL1 during Tetrahymena growth and conjugation. Iterative proteomics analyses revealed that the cell cycle regulatory MuvB-complex in Tetrahymena is composed of at least five subunits including evolutionarily conserved Lin54, Lin9 and RebL1 proteins. Genome-wide analyses indicated that RebL1 and Lin54 (Anqa1) bind within genic and intergenic regions. Moreover, Anqa1 targets primarily promoter regions suggesting a role for Tetrahymena MuvB in transcription regulation. RebL1 depletion inhibited cellular growth and reduced the expression levels of Anqa1 and Lin9. Consistent with observations in glioblastoma tumors, RebL1 depletion suppressed DNA repair protein Rad51 in Tetrahymena, thus underscoring the evolutionarily conserved functions of RBBP4/7 proteins. Our results suggest the essentiality of RebL1 functions in multiple epigenetic regulatory complexes in which it impacts transcription regulation and cellular viability.
Identifiants
pubmed: 34086947
pii: 6292101
doi: 10.1093/nar/gkab413
pmc: PMC8216455
doi:
Substances chimiques
Bacterial Proteins
0
DNA-Binding Proteins
0
H-NS protein, bacteria
0
Histone Chaperones
0
Histones
0
Protozoan Proteins
0
RBBP4 protein, human
0
RBBP7 protein, human
0
Retinoblastoma-Binding Protein 4
0
Retinoblastoma-Binding Protein 7
0
DNA
9007-49-2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6196-6212Subventions
Organisme : CIHR
ID : MOP13347
Pays : Canada
Informations de copyright
© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.
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