Heterochromatin protein 1

Last updated
chromobox homolog 5
Identifiers
Symbol CBX5
Alt. symbolsHP1-alpha
NCBI gene 23468
HGNC 1555
OMIM 604478
RefSeq NM_012117
UniProt P45973
Other data
Locus Chr. 12 q13.13
chromobox homolog 1
Identifiers
Symbol CBX1
Alt. symbolsHP1-beta
NCBI gene 10951
HGNC 1551
OMIM 604511
RefSeq NM_006807
UniProt P83916
Other data
Locus Chr. 17 q21.32
chromobox homolog 3
Identifiers
Symbol CBX3
Alt. symbolsHP1-gamma
NCBI gene 11335
HGNC 1553
OMIM 604477
RefSeq NM_007276
UniProt Q13185
Other data
Locus Chr. 7 p21-15

The family of heterochromatin protein 1 (HP1) ("Chromobox Homolog", CBX) consists of highly conserved proteins, which have important functions in the cell nucleus. These functions include gene repression by heterochromatin formation, transcriptional activation, regulation of binding of cohesion complexes to centromeres, sequestration of genes to the nuclear periphery, transcriptional arrest, maintenance of heterochromatin integrity, gene repression at the single nucleosome level, gene repression by heterochromatization of euchromatin, and DNA repair. HP1 proteins are fundamental units of heterochromatin packaging that are enriched at the centromeres and telomeres of nearly all eukaryotic chromosomes with the notable exception of budding yeast, in which a yeast-specific silencing complex of SIR (silent information regulatory) proteins serve a similar function. Members of the HP1 family are characterized by an N-terminal chromodomain and a C-terminal chromoshadow domain, separated by a hinge region. HP1 is also found at some euchromatic sites, where its binding can correlate with either gene repression or gene activation. HP1 was originally discovered by Tharappel C James and Sarah Elgin in 1986 as a factor in the phenomenon known as position effect variegation in Drosophila melanogaster . [1] [2]

Contents

Paralogs and orthologs

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]

HP1β in mammals

HP1β interacts with the histone methyltransferase (HMTase) Suv(3-9)h1 and is a component of both pericentric and telomeric heterochromatin. [5] [6] [7] HP1β is a dosage-dependent modifier of pericentric heterochromatin-induced silencing [8] and silencing is thought to involve a dynamic association of the HP1β chromodomain with the tri-methylated histone H3 K9me3. The binding of the K9me3-modified H3 N-terminal tail by the chromodomain is a defining feature of HP1 proteins.

Interacting proteins

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]

Binding affinity and cooperativity

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.

Role in DNA repair

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 (t1/2) by 180 seconds in response to UV damage, and a t1/2 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 t1/2 of 40 seconds for UV damage and a t1/2 of about 1 second in response to double-strand breaks (see DNA damage response).[ citation needed ]

See also

Related Research Articles

<span class="mw-page-title-main">Histone</span> Family proteins package and order the DNA into structural units called nucleosomes.

In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are wrapped into 30-nanometer fibers that form tightly packed chromatin. Histones prevent DNA from becoming tangled and protect it from DNA damage. In addition, histones play important roles in gene regulation and DNA replication. Without histones, unwound DNA in chromosomes would be very long. For example, each human cell has about 1.8 meters of DNA if completely stretched out; however, when wound about histones, this length is reduced to about 90 micrometers (0.09 mm) of 30 nm diameter chromatin fibers.

Histone methylation is a process by which methyl groups are transferred to amino acids of histone proteins that make up nucleosomes, which the DNA double helix wraps around to form chromosomes. Methylation of histones can either increase or decrease transcription of genes, depending on which amino acids in the histones are methylated, and how many methyl groups are attached. Methylation events that weaken chemical attractions between histone tails and DNA increase transcription because they enable the DNA to uncoil from nucleosomes so that transcription factor proteins and RNA polymerase can access the DNA. This process is critical for the regulation of gene expression that allows different cells to express different genes.

<span class="mw-page-title-main">Methyllysine</span> Derivative of the amino acid residue lysine

Methyllysine is derivative of the amino acid residue lysine where the sidechain ammonium group has been methylated one or more times.

<span class="mw-page-title-main">Chromodomain</span>

A chromodomain is a protein structural domain of about 40–50 amino acid residues commonly found in proteins associated with the remodeling and manipulation of chromatin. The domain is highly conserved among both plants and animals, and is represented in a large number of different proteins in many genomes, such as that of the mouse. Some chromodomain-containing genes have multiple alternative splicing isoforms that omit the chromodomain entirely. In mammals, chromodomain-containing proteins are responsible for aspects of gene regulation related to chromatin remodeling and formation of heterochromatin regions. Chromodomain-containing proteins also bind methylated histones and appear in the RNA-induced transcriptional silencing complex. In histone modifications, chromodomains are very conserved. They function by identifying and binding to methylated lysine residues that exist on the surface of chromatin proteins and thereby regulate gene transcription.

<span class="mw-page-title-main">CBX3</span> Protein-coding gene in the species Homo sapiens

Chromobox protein homolog 3 is a protein that is encoded by the CBX3 gene in humans.

Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out by 1) covalent histone modifications by specific enzymes, e.g., histone acetyltransferases (HATs), deacetylases, methyltransferases, and kinases, and 2) ATP-dependent chromatin remodeling complexes which either move, eject or restructure nucleosomes. Besides actively regulating gene expression, dynamic remodeling of chromatin imparts an epigenetic regulatory role in several key biological processes, egg cells DNA replication and repair; apoptosis; chromosome segregation as well as development and pluripotency. Aberrations in chromatin remodeling proteins are found to be associated with human diseases, including cancer. Targeting chromatin remodeling pathways is currently evolving as a major therapeutic strategy in the treatment of several cancers.

<span class="mw-page-title-main">SUV39H1</span> Protein-coding gene in the species Homo sapiens

Histone-lysine N-methyltransferase SUV39H1 is an enzyme that in humans is encoded by the SUV39H1 gene.

<span class="mw-page-title-main">Histone H3.1</span>

Histone H3.1 is a protein in humans that is encoded by the H3C1 gene.

<span class="mw-page-title-main">CHD1</span> Chromatin remodeling protein that is widely conserved across many eukaryotic organisms

The Chromodomain-Helicase DNA-binding 1 is a protein that, in humans, is encoded by the CHD1 gene. CHD1 is a chromatin remodeling protein that is widely conserved across many eukaryotic organisms, from yeast to humans. CHD1 is named for three of its protein domains: two tandem chromodomains, its ATPase catalytic domain, and its DNA-binding domain.

<span class="mw-page-title-main">CBX5 (gene)</span>

Chromobox protein homolog 5 is a protein that in humans is encoded by the CBX5 gene. It is a highly conserved, non-histone protein part of the heterochromatin family. The protein itself is more commonly called HP1α. Heterochromatin protein-1 (HP1) has an N-terminal domain that acts on methylated lysines residues leading to epigenetic repression. The C-terminal of this protein has a chromo shadow-domain (CSD) that is responsible for homodimerizing, as well as interacting with a variety of chromatin-associated, non-histone proteins.

<span class="mw-page-title-main">EHMT1</span> Protein-coding gene in the species Homo sapiens

Euchromatic histone-lysine N-methyltransferase 1, also known as G9a-like protein (GLP), is a protein that in humans is encoded by the EHMT1 gene.

H3K4me3 is an epigenetic modification to the DNA packaging protein Histone H3 that indicates tri-methylation at the 4th lysine residue of the histone H3 protein and is often involved in the regulation of gene expression. The name denotes the addition of three methyl groups (trimethylation) to the lysine 4 on the histone H3 protein.

H3K27me3 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the tri-methylation of lysine 27 on histone H3 protein.

<span class="mw-page-title-main">Thomas Jenuwein</span> German scientist

Thomas Jenuwein is a German scientist working in the fields of epigenetics, chromatin biology, gene regulation and genome function.

H3K9me3 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the tri-methylation at the 9th lysine residue of the histone H3 protein and is often associated with heterochromatin.

H3K36me3 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the tri-methylation at the 36th lysine residue of the histone H3 protein and often associated with gene bodies.

H4K20me is an epigenetic modification to the DNA packaging protein Histone H4. It is a mark that indicates the mono-methylation at the 20th lysine residue of the histone H4 protein. This mark can be di- and tri-methylated. It is critical for genome integrity including DNA damage repair, DNA replication and chromatin compaction.

H3K36me2 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the di-methylation at the 36th lysine residue of the histone H3 protein.

H3K36me is an epigenetic modification to the DNA packaging protein Histone H3, specifically, the mono-methylation at the 36th lysine residue of the histone H3 protein.

H3Y41P is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates the phosphorylation the 41st tyrosine residue of the histone H3 protein.

References

  1. ↑ James TC, Elgin SC (November 1986). "Identification of a nonhistone chromosomal protein associated with heterochromatin in Drosophila melanogaster and its gene". Molecular and Cellular Biology. 6 (11): 3862–72. doi:10.1128/mcb.6.11.3862. PMC   367149 . PMID   3099166.
  2. ↑ Eissenberg JC, James TC, Foster-Hartnett DM, Hartnett T, Ngan V, Elgin SC (December 1990). "Mutation in a heterochromatin-specific chromosomal protein is associated with suppression of position-effect variegation in Drosophila melanogaster". Proceedings of the National Academy of Sciences of the United States of America. 87 (24): 9923–7. Bibcode:1990PNAS...87.9923E. doi: 10.1073/pnas.87.24.9923 . PMC   55286 . PMID   2124708.
  3. ↑ Singh PB, Miller JR, Pearce J, Kothary R, Burton RD, Paro R, et al. (February 1991). "A sequence motif found in a Drosophila heterochromatin protein is conserved in animals and plants". Nucleic Acids Research. 19 (4): 789–94. doi:10.1093/nar/19.4.789. PMC   333712 . PMID   1708124.
  4. ↑ Kotake T, Takada S, Nakahigashi K, Ohto M, Goto K (June 2003). "Arabidopsis TERMINAL FLOWER 2 gene encodes a heterochromatin protein 1 homolog and represses both FLOWERING LOCUS T to regulate flowering time and several floral homeotic genes". Plant & Cell Physiology. 44 (6): 555–64. doi: 10.1093/pcp/pcg091 . PMID   12826620.
  5. ↑ Aagaard L, Laible G, Selenko P, Schmid M, Dorn R, Schotta G, et al. (April 1999). "Functional mammalian homologues of the Drosophila PEV-modifier Su(var)3-9 encode centromere-associated proteins which complex with the heterochromatin component M31". The EMBO Journal. 18 (7): 1923–38. doi:10.1093/emboj/18.7.1923. PMC   1171278 . PMID   10202156.
  6. ↑ Wreggett KA, Hill F, James PS, Hutchings A, Butcher GW, Singh PB (1994). "A mammalian homologue of Drosophila heterochromatin protein 1 (HP1) is a component of constitutive heterochromatin". Cytogenetics and Cell Genetics. 66 (2): 99–103. doi:10.1159/000133676. PMID   8287692.
  7. ↑ Sharma GG, Hwang KK, Pandita RK, Gupta A, Dhar S, Parenteau J, et al. (November 2003). "Human heterochromatin protein 1 isoforms HP1(Hsalpha) and HP1(Hsbeta) interfere with hTERT-telomere interactions and correlate with changes in cell growth and response to ionizing radiation". Molecular and Cellular Biology. 23 (22): 8363–76. doi:10.1128/MCB.23.22.8363-8376.2003. PMC   262350 . PMID   14585993.
  8. ↑ Festenstein R, Sharghi-Namini S, Fox M, Roderick K, Tolaini M, Norton T, et al. (December 1999). "Heterochromatin protein 1 modifies mammalian PEV in a dose- and chromosomal-context-dependent manner". Nature Genetics. 23 (4): 457–61. doi:10.1038/70579. PMID   10581035. S2CID   35664478.
  9. ↑ Kumar A, Kono H (April 2020). "Heterochromatin protein 1 (HP1): interactions with itself and chromatin components". Biophysical Reviews. 12 (2): 387–400. doi:10.1007/s12551-020-00663-y. PMC   7242596 . PMID   32144738.
  10. ↑ Prasanth SG, Shen Z, Prasanth KV, Stillman B (August 2010). "Human origin recognition complex is essential for HP1 binding to chromatin and heterochromatin organization". Proceedings of the National Academy of Sciences of the United States of America. 107 (34): 15093–8. Bibcode:2010PNAS..10715093P. doi: 10.1073/pnas.1009945107 . PMC   2930523 . PMID   20689044.
  11. ↑ Agarwal N, Hardt T, Brero A, Nowak D, Rothbauer U, Becker A, et al. (August 2007). "MeCP2 interacts with HP1 and modulates its heterochromatin association during myogenic differentiation". Nucleic Acids Research. 35 (16): 5402–8. doi:10.1093/nar/gkm599. PMC   2018631 . PMID   17698499.
  12. ↑ Verschure PJ, van der Kraan I, de Leeuw W, van der Vlag J, Carpenter AE, Belmont AS, van Driel R (June 2005). "In vivo HP1 targeting causes large-scale chromatin condensation and enhanced histone lysine methylation". Molecular and Cellular Biology. 25 (11): 4552–64. doi: 10.1128/mcb.25.11.4552-4564.2005 . PMC   1140641 . PMID   15899859.
  13. ↑ Lachner M, O'Carroll D, Rea S, Mechtler K, Jenuwein T (March 2001). "Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins". Nature. 410 (6824): 116–20. Bibcode:2001Natur.410..116L. doi:10.1038/35065132. PMID   11242053. S2CID   4331863.
  14. ↑ Teif VB, Kepper N, Yserentant K, Wedemann G, Rippe K (February 2015). "Affinity, stoichiometry and cooperativity of heterochromatin protein 1 (HP1) binding to nucleosomal arrays". Journal of Physics: Condensed Matter. 27 (6): 064110. arXiv: 1408.6184 . Bibcode:2015JPCM...27f4110T. doi:10.1088/0953-8984/27/6/064110. PMID   25563825. S2CID   1727121.
  15. ↑ Hodges C, Crabtree GR (August 2012). "Dynamics of inherently bounded histone modification domains". Proceedings of the National Academy of Sciences of the United States of America. 109 (33): 13296–301. Bibcode:2012PNAS..10913296H. doi: 10.1073/pnas.1211172109 . PMC   3421184 . PMID   22847427.
  16. ↑ Hathaway NA, Bell O, Hodges C, Miller EL, Neel DS, Crabtree GR (June 2012). "Dynamics and memory of heterochromatin in living cells". Cell. 149 (7): 1447–60. doi:10.1016/j.cell.2012.03.052. PMC   3422694 . PMID   22704655.
  17. 1 2 3 Yearim A, Gelfman S, Shayevitch R, Melcer S, Glaich O, Mallm JP, et al. (February 2015). "HP1 is involved in regulating the global impact of DNA methylation on alternative splicing". Cell Reports. 10 (7): 1122–34. doi: 10.1016/j.celrep.2015.01.038 . PMID   25704815.
  18. 1 2 Muro AF, Caputi M, Pariyarath R, Pagani F, Buratti E, Baralle FE (April 1999). "Regulation of fibronectin EDA exon alternative splicing: possible role of RNA secondary structure for enhancer display". Molecular and Cellular Biology. 19 (4): 2657–71. doi:10.1128/MCB.19.4.2657. PMC   84059 . PMID   10082532.
  19. ↑ Dinant C, Luijsterburg MS (December 2009). "The emerging role of HP1 in the DNA damage response". Molecular and Cellular Biology. 29 (24): 6335–40. doi:10.1128/MCB.01048-09. PMC   2786877 . PMID   19805510.
  20. 1 2 Bártová E, Malyšková B, Komůrková D, Legartová S, Suchánková J, Krejčí J, Kozubek S (May 2017). "Function of heterochromatin protein 1 during DNA repair". Protoplasma. 254 (3): 1233–1240. doi:10.1007/s00709-017-1090-3. PMID   28236007. S2CID   12094768.
  21. ↑ Luijsterburg MS, Dinant C, Lans H, Stap J, Wiernasz E, Lagerwerf S, et al. (May 2009). "Heterochromatin protein 1 is recruited to various types of DNA damage". The Journal of Cell Biology. 185 (4): 577–86. doi:10.1083/jcb.200810035. PMC   2711568 . PMID   19451271.

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