Abstract
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 HP1γ (CBX3) isoform, named here sHP1γ, generated by alternative splicing of the CBX3 locus. The sHP1γ 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 HP1γ protein. Fold recognition, order-to-disorder calculations, threading, homology-based molecular modeling, docking, and molecular dynamic simulations show that the sHP1γ 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 sHP1γ mRNA is expressed in the majority of human tissues at approximately constant ratios with the chromoshadow domain containing isoform. However, sHP1γ 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 HP1γ-mediated functions is more complex than previously anticipated.
Highlights
Heterochromatin protein 1 (HP1) is a cancer-associated chromatin protein, which was first identified as a major component of heterochromatin[1, 2]
The Chromobox containing protein 3 (CBX3) locus is located within human chromosome 7 and has 6 exons, and annotation of these gene transcripts is found on Ensembl/Havana (ENST00000409747 and OTTHUMT00000327972.1)
In this study, we report the existence of an additional 1717bp transcript which encodes a smaller protein of 101 amino acids that lacks the C-terminal chromoshadow domain (CSD) (Fig 1A and 1B), hereafter named short HP1γ. sHP1γ is generated by a splicing event that skips part of the fourth exon, shifts the reading frame and initiates a new stop codon in exon 5 (Fig 1C)
Summary
HP1 is a cancer-associated chromatin protein, which was first identified as a major component of heterochromatin[1, 2]. CSD dimerization leads to the formation of a docking motif, which is used by HP1 proteins to interact with large variety of chromatin regulators, typically through a PXVXL consensus motif[4]. These additional interactions allow the execution of complex-specific cancer-associated functions, including DNA recombination and repair, cell proliferation, differentiation, and migration, as well as chromosomal stability[4, 9]. The significant number of biochemical and biophysical studies that have been focused on defining the structure-function relationship of the different domains within HP1 have advanced our understanding of one of the most important families of proteins involved in epigenomic regulation
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