Heterochromatin protein 1

Three different paralogs of HP1 are found in Drosophila melanogaster, HP1a, HP1b and HP1c. Subsequently orthologs of HP1 were also discovered in S. pombe (Swi6), Xenopus (Xhp1α and Xhp1γ), Chicken (CHCB1, CHCB2 and CHCB3), Tetrahymena (Pdd1p) and many other metazoans. In mammals,[3] there are three paralogs: HP1α, HP1β and HP1γ. In Arabidopsis thaliana (a plant), there is one structural homolog: Like Heterochromatin Protein 1 (LHP1), also known as Terminal Flower 2 (TFL2).[4]

HP1 interacts with numerous other proteins/molecules (in addition to H3K9me3) with different cellular functions in different organisms. Some of these HP1 interacting partners are: histone H1, histone H3, histone H4, histone methyltransferase, DNA methyltransferase, methyl CpG binding protein MeCP2, and the origin recognition complex protein ORC2.[9][10][11]

HP1 has a versatile structure with three main components; a chromodomain, a chromoshadow domain, and a hinge domain.[12] The chromodomain is responsible for the specific binding affinity of HP1 to histone H3 when tri-methylated at the 9th lysine residue.[13] HP1 binding affinity to nucleosomes containing histone H3 methylated at lysine K9 is significantly higher than to those with unmethylated lysine K9. HP1 binds nucleosomes as a dimer and in principle can form multimeric complexes. Some studies have interpreted HP1 binding in terms of nearest-neighbor cooperative binding. However, the analysis of available data on HP1 binding to nucleosomal arrays in vitro shows that experimental HP1 binding isotherms can be explained by a simple model without cooperative interactions between neighboring HP1 dimers.[14] Nevertheless, favorable interactions between nearest neighbors of HP1 lead to limited spreading of HP1 and its marks along the nucleosome chain in vivo.[15][16]

The binding affinity of the HP1 chromodomain has also been implicated in regulation of alternative splicing.[17] HP1 can act as both an enhancer and silencer of splicing alternative exons. The exact role it plays in regulation varies by gene and is dependent on the methylation patterns within the gene body.[17] In humans, the role of HP1 on splicing has been characterized for alternative splicing of the EDA exon from the fibronectin gene. In this pathway HP1 acts as a mediator protein for repression of alternative splicing of the EDA exon.[18] When the chromatin within the gene body is not methylated, HP1 does not bind and the EDA exon is transcribed. When the chromatin is methylated, HP1 binds the chromatin and recruits the splicing factor SRSF3 which binds HP1 and splices the EDA exon from the mature transcript.[17][18] In this mechanism HP1 recognizes the H3K9me3 methylated chromatin and recruits a splicing factor to alternatively splice the mRNA, thereby excluding the EDA exon from the mature transcript.

All HP1 isoforms (HP1-alpha, HP1-beta, and HP1-gamma) are recruited to DNA at sites of UV-induced damages, at oxidative damages and at DNA breaks.[19] The HP1 protein isoforms are required for DNA repair of these damages.[20] The presence of the HP1 protein isoforms at DNA damages assists with the recruitment of other proteins involved in subsequent DNA repair pathways.[20] The recruitment of the HP1 isoforms to DNA damage is rapid, with half maximum recruitment (t_1/2) by 180 seconds in response to UV damage, and a t_1/2 of 85 seconds in response to double-strand breaks.[21] This is a bit slower than the recruitment of the very earliest proteins recruited to sites of DNA damage, though HP1 recruitment is still one of the very early steps in DNA repair. Other earlier proteins may be recruited with a t_1/2 of 40 seconds for UV damage and a t_1/2 of about 1 second in response to double-strand breaks (see DNA damage response).

• Epigenetics
• nucleosome
• Heterochromatin