CBX5 (gene)

Chromobox protein homolog 5 is a protein that in humans is encoded by the CBX5 gene.[5][6] It is a highly conserved, non-histone protein part of the heterochromatin family. The protein itself is more commonly called (in humans) HP1α. Heterochromatin protein-1 (HP1) has an N-terminal domain that acts on methylated lysines residues leading to epigenetic repression.[7] 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.[8]

CBX5
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3FDT, 3I3C
Identifiers
Aliases	CBX5, HEL25, HP1, HP1A, chromobox 5
External IDs	OMIM: 604478 MGI: 109372 HomoloGene: 7257 GeneCards: CBX5
Gene location (Human) Chr. Chromosome 12 (human)[1] Band 12q13.13 Start 54,230,942 bp[1] End 54,280,133 bp[1]
Gene location (Mouse) Chr. Chromosome 15 (mouse)[2] Band 15|15 F3 Start 103,191,544 bp[2] End 103,239,816 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • protein homodimerization activity • repressing transcription factor binding • GO:0001948 protein binding • protein binding, bridging • chromatin binding • histone deacetylase binding • methylated histone binding • ribonucleoprotein complex binding • GO:0032403 macromolecular complex binding • identical protein binding Cellular component • nuclear pericentric heterochromatin • kinetochore • cell nucleus • nuclear envelope • pericentric heterochromatin • nucleolus • histone deacetylase complex • nucleoplasm • nuclear chromosome, telomeric region • chromocenter • heterochromatin • chromosome, centromeric region • histone methyltransferase complex • transcriptional repressor complex • chromosome • nuclear heterochromatin • PML body • macromolecular complex • ribonucleoprotein • site of DNA damage Biological process • blood coagulation • negative regulation of transcription, DNA-templated • GO:0022415 viral process • negative regulation of transcription from RNA polymerase II promoter • negative regulation of G0 to G1 transition • cellular response to DNA damage stimulus Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	23468	12419
Ensembl	ENSG00000094916	ENSMUSG00000009575
UniProt	P45973	Q61686
RefSeq (mRNA)	NM_012117 NM_001127321 NM_001127322	NM_001076789 NM_001110216 NM_007626 NM_001358950
RefSeq (protein)	NP_001120793 NP_001120794 NP_036249	NP_001070257 NP_001103686 NP_031652 NP_001345879
Location (UCSC)	Chr 12: 54.23 – 54.28 Mb	Chr 15: 103.19 – 103.24 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Structure

HP1α is 191 amino acids in length containing 6 exons.[7][8] As mentioned above, this protein contains two domains, an N-terminal chromodomain (CD) and a C- terminal chromoshadow domain (CSD). The CD binds with histone 3 through a methylated lysine residue at position 9 (H3K9) while the C-terminal CSD homodimerizes and interacts with a variety of other chromatin-associated, non-histone related proteins.[8] Connecting these two domains is the hinge region.[9]

Chromodomain

Once translated, the chromodomain will take on a globular conformation consisting of three β-sheets and one α-helix. The β-sheets are packed up against the helix at the carboxy terminal segment.[9] The charges on the β sheets are negative thus making it difficult for it to bind to the DNA as a DNA-binding motif. Instead, HP1α binds to the histones as a protein interaction motif.[8] Specific binding to CD to the methylated H3K9 is mediated by three hydrophobic side chains called the "hydrophobic box". Other sites on HP1 will interact with the H3 tails from neighbouring histones which will give structure to the flexible N-terminal tail of the histones. Neighbouring H3 histones can affect HP1 binding by post-translationally modifying the tails.[9]

Chromoshadow domain

The CSD much resembles that of the CD. It too has a globular conformation containing three β-sheets, however it possesses two α-helices as opposed to just the one in the CD.[9] The CSD readily homodimerizes in vitro and as a result forms a groove which can accommodate HP1 associated proteins that have a specific consensus sequence: PxVxL, where P is Proline, V is Valine, L is Leucine and x is any amino acid.[8]

Mechanism of action

HP1α primarily functions as a gene silencer, which is dependent on the interactions between the CD and the methyl H3K9 mark.[10] The hydrophobic box on the CD provides the appropriate environment for the methylated lysine residue. While the exact mechanism of how gene silencing is done is unknown, experimental data concluded the rapid exchange of biological macromolecules in and out of the heterochromatin region. This suggests HP1 isn't acting as a glue holding the heterochromatin together, but rather there are competing molecules within that interact in various ways to create a closed complex leading to gene repression or an open, euchromatin structure with gene activation. HP1 concentration is higher and more static in areas of the chromosome where methylated H3K9 residues reside, giving the chromosome its closed, gene-repressed heterochromatin structure.[9] It has also been shown that the more methylated the H3 lysine is, the higher the affinity HP1 has for it. That is, trimethylated lysine residues bind tighter to HP1 than dimethylated residues, which bind better than monomethylated residues.

The localisation driving factor is currently unknown.[9]

Evolutionary conservation

HP1α is a highly evolutionary conserved protein, existing in species such a Schizosaccharomyces pombe, a type of yeast, all the way to humans.[9] The N-terminal chromodomain and C-terminal chromoshadow domain appear to be much more conserved (approximately 50-70% amino acid similarity) than the hinge region (approximately 25-30% similarity with the Drosophila HP1 homolog).[9]

Interactions

CBX5 (gene) has been shown to interact with:

• CBX1,[11]
• CBX3,[11]
• CHAF1A,[12][13]
• DNMT3B,[14]
• HDAC4,[15]
• HDAC9,[15]
• Histone deacetylase 5,[15]
• Ku70,[16]
• Lamin B receptor,[17]
• MBD1,[12][18]
• MIS12,[19]
• SMARCA4,[20]
• SUV39H1,[15][18][21]
• TAF4,[22] and
• TRIM28.[11][13][20][23]
• STAT5A,[24]

See also

• Heterochromatin protein 1

References

1. GRCh38: Ensembl release 89: ENSG00000094916 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000009575 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Ye Q, Worman HJ (Jun 1996). "Interaction between an integral protein of the nuclear envelope inner membrane and human chromodomain proteins homologous to Drosophila HP1". The Journal of Biological Chemistry. 271 (25): 14653–6. doi:10.1074/jbc.271.25.14653. PMID 8663349.
6. "Entrez Gene: CBX5 chromobox homolog 5 (HP1 alpha homolog, Drosophila)".
7. "OMIM Entry- * 604478 - CHROMOBOX HOMOLOG 5; CBX5". omim.org. Retrieved 2015-11-02.
8. Lomberk G, Wallrath L, Urrutia R (2006). "The heterochromatin protein 1 family". Genome Biol. 7 (7): 228. doi:10.1186/gb-2006-7-7-228. PMC 1779566. PMID 17224041.
9. Hiragami, K (15 August 2005). "Heterochromatin Protein 1: a pervasive controlling influence". Cellular and Molecular Life Sciences. 62 (23): 2711–2726. doi:10.1007/s00018-005-5287-9. PMID 16261261.
10. "CBX5 chromobox homolog 5 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2015-10-16.
11. Nielsen AL, Oulad-Abdelghani M, Ortiz JA, Remboutsika E, Chambon P, Losson R (Apr 2001). "Heterochromatin formation in mammalian cells: interaction between histones and HP1 proteins". Molecular Cell. 7 (4): 729–39. doi:10.1016/S1097-2765(01)00218-0. PMID 11336697.
12. Reese BE, Bachman KE, Baylin SB, Rountree MR (May 2003). "The methyl-CpG binding protein MBD1 interacts with the p150 subunit of chromatin assembly factor 1". Molecular and Cellular Biology. 23 (9): 3226–36. doi:10.1128/mcb.23.9.3226-3236.2003. PMC 153189. PMID 12697822.
13. Lechner MS, Begg GE, Speicher DW, Rauscher FJ (Sep 2000). "Molecular determinants for targeting heterochromatin protein 1-mediated gene silencing: direct chromoshadow domain-KAP-1 corepressor interaction is essential". Molecular and Cellular Biology. 20 (17): 6449–65. doi:10.1128/mcb.20.17.6449-6465.2000. PMC 86120. PMID 10938122.
14. Lehnertz B, Ueda Y, Derijck AA, Braunschweig U, Perez-Burgos L, Kubicek S, Chen T, Li E, Jenuwein T, Peters AH (Jul 2003). "Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin". Current Biology. 13 (14): 1192–200. doi:10.1016/s0960-9822(03)00432-9. PMID 12867029.
15. Zhang CL, McKinsey TA, Olson EN (Oct 2002). "Association of class II histone deacetylases with heterochromatin protein 1: potential role for histone methylation in control of muscle differentiation". Molecular and Cellular Biology. 22 (20): 7302–12. doi:10.1128/mcb.22.20.7302-7312.2002. PMC 139799. PMID 12242305.
16. Song K, Jung Y, Jung D, Lee I (Mar 2001). "Human Ku70 interacts with heterochromatin protein 1alpha". The Journal of Biological Chemistry. 276 (11): 8321–7. doi:10.1074/jbc.M008779200. PMID 11112778.
17. Ye Q, Worman HJ (Jun 1996). "Interaction between an integral protein of the nuclear envelope inner membrane and human chromodomain proteins homologous to Drosophila HP1". The Journal of Biological Chemistry. 271 (25): 14653–6. doi:10.1074/jbc.271.25.14653. PMID 8663349.
18. Fujita N, Watanabe S, Ichimura T, Tsuruzoe S, Shinkai Y, Tachibana M, Chiba T, Nakao M (Jun 2003). "Methyl-CpG binding domain 1 (MBD1) interacts with the Suv39h1-HP1 heterochromatic complex for DNA methylation-based transcriptional repression". The Journal of Biological Chemistry. 278 (26): 24132–8. doi:10.1074/jbc.M302283200. PMID 12711603.
19. Obuse C, Iwasaki O, Kiyomitsu T, Goshima G, Toyoda Y, Yanagida M (Nov 2004). "A conserved Mis12 centromere complex is linked to heterochromatic HP1 and outer kinetochore protein Zwint-1". Nature Cell Biology. 6 (11): 1135–41. doi:10.1038/ncb1187. PMID 15502821.
20. Nielsen AL, Sanchez C, Ichinose H, Cerviño M, Lerouge T, Chambon P, Losson R (Nov 2002). "Selective interaction between the chromatin-remodeling factor BRG1 and the heterochromatin-associated protein HP1alpha". The EMBO Journal. 21 (21): 5797–806. doi:10.1093/emboj/cdf560. PMC 131057. PMID 12411497.
21. Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M (Oct 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. doi:10.1038/nature04209. PMID 16189514.
22. Vassallo MF, Tanese N (Apr 2002). "Isoform-specific interaction of HP1 with human TAFII130". Proceedings of the National Academy of Sciences of the United States of America. 99 (9): 5919–24. doi:10.1073/pnas.092025499. PMC 122877. PMID 11959914.
23. Cammas F, Oulad-Abdelghani M, Vonesch JL, Huss-Garcia Y, Chambon P, Losson R (Sep 2002). "Cell differentiation induces TIF1beta association with centromeric heterochromatin via an HP1 interaction". Journal of Cell Science. 115 (Pt 17): 3439–48. PMID 12154074.
24. Hu X, Dutta P, Tsurumi A, Li J, Wang J, Land H, Li WX (Jun 2013). "Unphosphorylated STAT5A stabilizes heterochromatin and suppresses tumor growth". Proc Natl Acad Sci U S A. 110 (25): 10213–10218. doi:10.1073/pnas.1221243110. PMC 3690839. PMID 23733954.

Further reading

• Saunders WS, Chue C, Goebl M, Craig C, Clark RF, Powers JA, Eissenberg JC, Elgin SC, Rothfield NF, Earnshaw WC (Feb 1993). "Molecular cloning of a human homologue of Drosophila heterochromatin protein HP1 using anti-centromere autoantibodies with anti-chromo specificity". Journal of Cell Science. 104 (2): 573–82. PMID 8505380.
• Sugimoto K, Yamada T, Muro Y, Himeno M (Jul 1996). "Human homolog of Drosophila heterochromatin-associated protein 1 (HP1) is a DNA-binding protein which possesses a DNA-binding motif with weak similarity to that of human centromere protein C (CENP-C)". Journal of Biochemistry. 120 (1): 153–9. doi:10.1093/oxfordjournals.jbchem.a021378. PMID 8864858.
• Ye Q, Callebaut I, Pezhman A, Courvalin JC, Worman HJ (Jun 1997). "Domain-specific interactions of human HP1-type chromodomain proteins and inner nuclear membrane protein LBR". The Journal of Biological Chemistry. 272 (23): 14983–9. doi:10.1074/jbc.272.23.14983. PMID 9169472.
• Lessard J, Baban S, Sauvageau G (Feb 1998). "Stage-specific expression of polycomb group genes in human bone marrow cells". Blood. 91 (4): 1216–24. PMID 9454751.
• Ainsztein AM, Kandels-Lewis SE, Mackay AM, Earnshaw WC (Dec 1998). "INCENP centromere and spindle targeting: identification of essential conserved motifs and involvement of heterochromatin protein HP1". The Journal of Cell Biology. 143 (7): 1763–74. doi:10.1083/jcb.143.7.1763. PMC 2175214. PMID 9864353.
• Minc E, Allory Y, Worman HJ, Courvalin JC, Buendia B (Aug 1999). "Localization and phosphorylation of HP1 proteins during the cell cycle in mammalian cells". Chromosoma. 108 (4): 220–34. doi:10.1007/s004120050372. PMID 10460410.
• Murzina N, Verreault A, Laue E, Stillman B (Oct 1999). "Heterochromatin dynamics in mouse cells: interaction between chromatin assembly factor 1 and HP1 proteins". Molecular Cell. 4 (4): 529–40. doi:10.1016/S1097-2765(00)80204-X. PMID 10549285.
• Nielsen AL, Ortiz JA, You J, Oulad-Abdelghani M, Khechumian R, Gansmuller A, Chambon P, Losson R (Nov 1999). "Interaction with members of the heterochromatin protein 1 (HP1) family and histone deacetylation are differentially involved in transcriptional silencing by members of the TIF1 family". The EMBO Journal. 18 (22): 6385–95. doi:10.1093/emboj/18.22.6385. PMC 1171701. PMID 10562550.
• Zhao T, Heyduk T, Allis CD, Eissenberg JC (Sep 2000). "Heterochromatin protein 1 binds to nucleosomes and DNA in vitro". The Journal of Biological Chemistry. 275 (36): 28332–8. doi:10.1074/jbc.M003493200. PMID 10882726.
• Lechner MS, Begg GE, Speicher DW, Rauscher FJ (Sep 2000). "Molecular determinants for targeting heterochromatin protein 1-mediated gene silencing: direct chromoshadow domain-KAP-1 corepressor interaction is essential". Molecular and Cellular Biology. 20 (17): 6449–65. doi:10.1128/MCB.20.17.6449-6465.2000. PMC 86120. PMID 10938122.
• Song K, Jung Y, Jung D, Lee I (Mar 2001). "Human Ku70 interacts with heterochromatin protein 1alpha". The Journal of Biological Chemistry. 276 (11): 8321–7. doi:10.1074/jbc.M008779200. PMID 11112778.
• Lachner M, O'Carroll D, Rea S, Mechtler K, Jenuwein T (Mar 2001). "Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins". Nature. 410 (6824): 116–20. doi:10.1038/35065132. PMID 11242053.
• Bannister AJ, Zegerman P, Partridge JF, Miska EA, Thomas JO, Allshire RC, Kouzarides T (Mar 2001). "Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain". Nature. 410 (6824): 120–4. doi:10.1038/35065138. PMID 11242054.
• Nielsen AL, Oulad-Abdelghani M, Ortiz JA, Remboutsika E, Chambon P, Losson R (Apr 2001). "Heterochromatin formation in mammalian cells: interaction between histones and HP1 proteins". Molecular Cell. 7 (4): 729–39. doi:10.1016/S1097-2765(01)00218-0. PMID 11336697.
• Wheatley SP, Carvalho A, Vagnarelli P, Earnshaw WC (Jun 2001). "INCENP is required for proper targeting of Survivin to the centromeres and the anaphase spindle during mitosis". Current Biology. 11 (11): 886–90. doi:10.1016/S0960-9822(01)00238-X. PMID 11516652.
• Scholzen T, Endl E, Wohlenberg C, van der Sar S, Cowell IG, Gerdes J, Singh PB (Feb 2002). "The Ki-67 protein interacts with members of the heterochromatin protein 1 (HP1) family: a potential role in the regulation of higher-order chromatin structure". The Journal of Pathology. 196 (2): 135–44. doi:10.1002/path.1016. PMID 11793364.
• Weinmann AS, Yan PS, Oberley MJ, Huang TH, Farnham PJ (Jan 2002). "Isolating human transcription factor targets by coupling chromatin immunoprecipitation and CpG island microarray analysis". Genes & Development. 16 (2): 235–44. doi:10.1101/gad.943102. PMC 155318. PMID 11799066.
• Sugimoto K, Tasaka H, Dotsu M (Dec 2001). "Molecular behavior in living mitotic cells of human centromere heterochromatin protein HPLalpha ectopically expressed as a fusion to red fluorescent protein". Cell Structure and Function. 26 (6): 705–18. doi:10.1247/csf.26.705. PMID 11942629.
• Vassallo MF, Tanese N (Apr 2002). "Isoform-specific interaction of HP1 with human TAFII130". Proceedings of the National Academy of Sciences of the United States of America. 99 (9): 5919–24. doi:10.1073/pnas.092025499. PMC 122877. PMID 11959914.

External links

• Human CBX5 genome location and CBX5 gene details page in the UCSC Genome Browser.