Heterochromatin protein 1
|chromobox homolog 5|
|Locus||Chr. 12 q13.13|
|chromobox homolog 1|
|Locus||Chr. 17 q21.32|
|chromobox homolog 3|
|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 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 euchromatic sites, where its binding correlates with gene repression. 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.
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) and Chicken (CHCB1, CHCB2 and CHCB3) and Tetrahymena (Pdd1p). In mammals, there are three paralogs: HP1α, HP1β and HP1γ. In Arabidopsis thaliana (a plant), there is one homolog: Like Heterochromatin Protein 1 (LHP1), also known as Terminal Flower 2 (TFL2).
HP1β in mammals
HP1β interacts with the histone methyltransferase (HMTase) Suv(3-9)h1 and is a component of both pericentric and telomeric heterochromatin. HP1β is a dosage-dependent modifier of pericentric heterochromatin-induced silencing and silencing is thought to involve a dynamic association of the HP1β chromodomain with the tri-methylated Histone H3 Me(3)K9H3.
HP1 seems to interact with numerous other proteins/molecules with different cellular functions in different organisms. Some of these HP1 interacting partners are: histone H1, histone H3, methylated K9 histone H3, histone H4, histone methyltransferase, DNA methyltransferase, methyl CpG binding protein MeCP2, and the origin recognition complex protein ORC2
Binding affinity and cooperativity
HP1 binding affinity to nucleosomes containing histone H3 methylated at lysine K9 is 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. Nevertheless, favorable interactions between nearest neighbors of HP1 lead to limited spreading of HP1 and its marks along the nucleosome chain in vivo.
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. The HP1 protein isoforms are required for DNA repair of these damages. The presence of the HP1 protein isoforms at DNA damages assists with the recruitment of other proteins involved in subsequent DNA repair pathways. 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. 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).
- 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.
- 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.
- Singh PB, Miller JR, Pearce J, Kothary R, Burton RD, Paro R, James TC, Gaunt SJ (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.
- 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.
- Aagaard L, Laible G, Selenko P, Schmid M, Dorn R, Schotta G, Kuhfittig S, Wolf A, Lebersorger A, Singh PB, Reuter G, Jenuwein T (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.
- 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.
- Sharma GG, Hwang KK, Pandita RK, Gupta A, Dhar S, Parenteau J, Agarwal M, Worman HJ, Wellinger RJ, Pandita TK (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.
- Festenstein R, Sharghi-Namini S, Fox M, Roderick K, Tolaini M, Norton T, Saveliev A, Kioussis D, Singh P (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.
- Teif V.B.; Kepper N.; Yserentant K; Wedemann G.; Rippe K. (2014). "Affinity, stoichiometry and cooperativity of heterochromatin protein 1 (HP1) binding to nucleosomal arrays". J. Phys.: Condens. Matter. 27 (6): 064110. arXiv:1408.6184. Bibcode:2015JPCM...27f4110T. doi:10.1088/0953-8984/27/6/064110. PMID 25563825. S2CID 1727121.
- 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.
- 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.
- Dinant C, Luijsterburg MS (December 2009). "The emerging role of HP1 in the DNA damage response". Mol. Cell. Biol. 29 (24): 6335–40. doi:10.1128/MCB.01048-09. PMC 2786877. PMID 19805510.
- 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.
- Luijsterburg MS, Dinant C, Lans H, Stap J, Wiernasz E, Lagerwerf S, Warmerdam DO, Lindh M, Brink MC, Dobrucki JW, Aten JA, Fousteri MI, Jansen G, Dantuma NP, Vermeulen W, Mullenders LH, Houtsmuller AB, Verschure PJ, van Driel R (May 2009). "Heterochromatin protein 1 is recruited to various types of DNA damage" (PDF). J. Cell Biol. 185 (4): 577–86. doi:10.1083/jcb.200810035. PMC 2711568. PMID 19451271.