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Heterochromatin protein 1

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chromobox homolog 5
Identifiers
SymbolCBX5
Alt. symbolsHP1-alpha
NCBI gene23468
HGNC1555
OMIM604478
RefSeqNM_012117
UniProtP45973
Other data
LocusChr. 12 q13.13
Search for
StructuresSwiss-model
DomainsInterPro
chromobox homolog 1
Identifiers
SymbolCBX1
Alt. symbolsHP1-beta
NCBI gene10951
HGNC1551
OMIM604511
RefSeqNM_006807
UniProtP83916
Other data
LocusChr. 17 q21.32
Search for
StructuresSwiss-model
DomainsInterPro
chromobox homolog 3
Identifiers
SymbolCBX3
Alt. symbolsHP1-gamma
NCBI gene11335
HGNC1553
OMIM604477
RefSeqNM_007276
UniProtQ13185
Other data
LocusChr. 7 p21-15
Search for
StructuresSwiss-model
DomainsInterPro

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]

Paralogs and orthologs

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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

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Main article: CBX1

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

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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

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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

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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

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References

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  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. ^ a b c 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. ^ a b 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. ^ a b 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.

Further reading

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