Discovery, expression, cellular localization, and molecular properties of a novel, alternative spliced HP1[gamma] isoform, lacking the chromoshadow domain

By reading the H3K9Me3 mark through their N-terminal chromodomain (CD), HP1 proteins play a significant role in cancer-associated processes, including cell proliferation, differentiation, chromosomal stability, and DNA repair. Here, we used a combination of bioinformatics-based methodologies, as wel...

Full description

Saved in:
Bibliographic Details
Published in:PloS one 2020-02, Vol.15 (2), p.e0217452
Main Authors: Mathison, Angela, Milech De Assuncao, Thiago, Dsouza, Nikita R, Williams, Monique, Zimmermann, Michael T, Urrutia, Raul, Lomberk, Gwen
Format: Article
Language:English
Subjects:
Analysis
Cancer
Cell differentiation
Computational biology
DNA
DNA repair
Messenger RNA
Molecular dynamics
Novels
Proteins
RNA
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:By reading the H3K9Me3 mark through their N-terminal chromodomain (CD), HP1 proteins play a significant role in cancer-associated processes, including cell proliferation, differentiation, chromosomal stability, and DNA repair. Here, we used a combination of bioinformatics-based methodologies, as well as experimentally-derived datasets, that reveal the existence of a novel short HP1[gamma] (CBX3) isoform, named here sHP1[gamma], generated by alternative splicing of the CBX3 locus. The sHP1[gamma] mRNA encodes a protein composed of 101 residues and lacks the C-terminal chromoshadow domain (CSD) that is required for dimerization and heterodimerization in the previously described 183 a. a HP1[gamma] protein. Fold recognition, order-to-disorder calculations, threading, homology-based molecular modeling, docking, and molecular dynamic simulations show that the sHP1[gamma] is comprised of a CD flanked by intrinsically disordered regions (IDRs) with an IDR-CD-IDR domain organization and likely retains the ability to bind to the H3K9Me3. Both qPCR analyses and mRNA-seq data derived from large-scale studies confirmed that sHP1[gamma] mRNA is expressed in the majority of human tissues at approximately constant ratios with the chromoshadow domain containing isoform. However, sHP1[gamma] mRNA levels appear to be dysregulated in different cancer types. Thus, our data supports the notion that, due to the existence of functionally different isoforms, the regulation of HP1[gamma]-mediated functions is more complex than previously anticipated.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0217452