CHD1

Last updated
CHD1
Protein CHD1 PDB 2b2t.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases CHD1 , chromodomain helicase DNA binding protein 1, PILBOS, CHD-1
External IDs OMIM: 602118 MGI: 88393 HomoloGene: 68174 GeneCards: CHD1
Orthologs
SpeciesHumanMouse
Entrez

1105

12648

Ensembl

ENSG00000153922

ENSMUSG00000023852

UniProt

O14646

P40201

RefSeq (mRNA)

NM_001270
NM_001364113
NM_001376194

NM_007690

RefSeq (protein)

NP_001261
NP_001351042
NP_001363123

NP_031716

Location (UCSC) Chr 5: 98.85 – 98.93 Mb Chr 17: 15.93 – 15.99 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

The Chromodomain-Helicase DNA-binding 1 is a protein that, in humans, is encoded by the CHD1 gene. [5] [6] [7] 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 (Figure 1). [8] [9]

The CHD1 remodeler binds nucleosomes and induces local changes in nucleosome positioning through ATP hydrolysis coupled to DNA translocation of the DNA across the histone proteins. [8] The catalytic domain of CHD1, which is highly conserved across all nucleosome remodelers, is a two-lobed structure. [8] CHD1 relies on the DNA-binding domain, which binds DNA in a sequence non-specific manner, to help regulate spacing. [10]

CHD1 is a member of a large family of CHD nucleosome remodelers, though yeast has only one CHD protein, called Chd1. [11] Humans and mice, by contrast, have ten CHD proteins that are homologous to CHD1, but each have their own characteristic functions. [11] [12]

Structure

CHD1 contains two tandem N-terminal chromodomains, a SNF2-related domain, a helicase C domain, CDH1/2 SANT-Helical linker, and a disordered C-terminal region. [13]

Figure 1. Schematic of the Chd1 protein, with tandem chromodomains (purple), ATPase catalytic domain (orange) and DNA binding domain (pink) bound to the nucleosome (DNA in blue, histones in green). Chd1 protein schematic.png
Figure 1. Schematic of the Chd1 protein, with tandem chromodomains (purple), ATPase catalytic domain (orange) and DNA binding domain (pink) bound to the nucleosome (DNA in blue, histones in green).

The structure of Chd1 bound to the nucleosome has been solved (Figure 2). [9]

Figure 2. Cryo-EM structure of Chd1 bound to the nucleosome, including the chromodomains (purple), ATPase domain (orange) and DNA-binding domain (pink), with histone octamer (green) and DNA (blue). PDB: 5O9G. CHD1 structure PDB 5O9G.png
Figure 2. Cryo-EM structure of Chd1 bound to the nucleosome, including the chromodomains (purple), ATPase domain (orange) and DNA-binding domain (pink), with histone octamer (green) and DNA (blue). PDB: 5O9G.

Function

CHD1 is essential for embryonic stem cell pluripotency in mice by maintaining an open euchromatic chromatin state. [14] Chd1 helps maintain boundaries between histone modifications H3K4me3 and H3K36me3. [15] It has also been shown that CHD1 is important in dictating the transcriptional landscape by promoting differentiation of osteoblasts, or differentiating bone cells. [16] Studies in both yeast and humans have found that Chd1 is recruited to DNA damage sites, where it promotes the opening of chromatin and the recruitment of DNA repair factors, thus facilitating DNA repair by homologous recombination. [17] [18]

Interactions

CHD1 has several genetic interactions with numerous factors involved in chromatin maintenance and transcription. Notably, the chromodomains of human CHD1 are capable of binding the histone modification histone H3 Lysine 4 trimethyl (H3K4me3). [19] It is thought that human CHD1 preferentially binds this histone modification, which is primarily located at the 5’ regions of genes, as a mechanism of recruitment to those genomic loci. However, in yeast it has been shown that Chd1 interacts with Rtf1, a transcription elongation factor and member of the Paf1 Complex (Paf1C). [20] Structural information has shown that the Chd1 chromodomains in yeast do not bind H3K4me3. [11]

CHD1 has been shown to interact with Nuclear receptor co-repressor 1. [21]

Clinical significance

CHD1 is most notably implicated in prostate cancer development. In about 10% of all prostate cancers, CHD1 is mutated or deleted. [22] [23] In prostate cancer cells CHD1 also has an essential relationship with another cancer driver, the PTEN locus. In studies of prostate cancer patient data, when PTEN is mutated, Chd1 gains an essential role and is never deleted. [22] Thus, CHD1 misfunction is evident in the majority of prostate cancers. Further, mutation of CHD1 alone is sufficient in some mice models to induce prostate tumorigenesis. [24]

Related Research Articles

Chromatin is a complex of DNA and protein found in eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in reinforcing the DNA during cell division, preventing DNA damage, and regulating gene expression and DNA replication. During mitosis and meiosis, chromatin facilitates proper segregation of the chromosomes in anaphase; the characteristic shapes of chromosomes visible during this stage are the result of DNA being coiled into highly condensed chromatin.

<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 and in most Archaeal phyla. 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.

<span class="mw-page-title-main">Nucleosome</span> Basic structural unit of DNA packaging in eukaryotes

A nucleosome is the basic structural unit of DNA packaging in eukaryotes. The structure of a nucleosome consists of a segment of DNA wound around eight histone proteins and resembles thread wrapped around a spool. The nucleosome is the fundamental subunit of chromatin. Each nucleosome is composed of a little less than two turns of DNA wrapped around a set of eight proteins called histones, which are known as a histone octamer. Each histone octamer is composed of two copies each of the histone proteins H2A, H2B, H3, and H4.

<span class="mw-page-title-main">Histone acetyltransferase</span> Enzymes that catalyze acyl group transfer from acetyl-CoA to histones

Histone acetyltransferases (HATs) are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl-CoA to form ε-N-acetyllysine. DNA is wrapped around histones, and, by transferring an acetyl group to the histones, genes can be turned on and off. In general, histone acetylation increases gene expression.

<span class="mw-page-title-main">S phase</span> DNA replication phase of the cell cycle, between G1 and G2 phase

S phase (Synthesis phase) is the phase of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Since accurate duplication of the genome is critical to successful cell division, the processes that occur during S-phase are tightly regulated and widely conserved.

HMGN proteins are members of the broader class of high mobility group (HMG) chromosomal proteins that are involved in regulation of transcription, replication, recombination, and DNA repair.

<span class="mw-page-title-main">SWI/SNF</span> Subfamily of ATP-dependent chromatin remodeling complexes

In molecular biology, SWI/SNF, is a subfamily of ATP-dependent chromatin remodeling complexes, which is found in eukaryotes. In other words, it is a group of proteins that associate to remodel the way DNA is packaged. This complex is composed of several proteins – products of the SWI and SNF genes, as well as other polypeptides. It possesses a DNA-stimulated ATPase activity that can destabilize histone-DNA interactions in reconstituted nucleosomes in an ATP-dependent manner, though the exact nature of this structural change is unknown. The SWI/SNF subfamily provides crucial nucleosome rearrangement, which is seen as ejection and/or sliding. The movement of nucleosomes provides easier access to the chromatin, allowing genes to be activated or repressed.

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.

The family of heterochromatin protein 1 (HP1) 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 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.

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">CHD3</span> Protein-coding gene in the species Homo sapiens

Chromodomain-helicase-DNA-binding protein 3 is an enzyme that in humans is encoded by the CHD3 gene.

<span class="mw-page-title-main">CHD4</span> Protein-coding gene in the species Homo sapiens

Chromodomain-helicase-DNA-binding protein 4 is an enzyme that in humans is encoded by the CHD4 gene. CHD4 is the core nucleosome-remodelling component of the Nucleosome Remodelling and Deacetylase (NuRD) complex.

<span class="mw-page-title-main">CHD8</span> Protein-coding gene in the species Homo sapiens

Chromodomain-helicase-DNA-binding protein 8 is an enzyme that in humans is encoded by the CHD8 gene.

In the field of molecular biology, the Mi-2/NuRDcomplex, is a group of associated proteins with both ATP-dependent chromatin remodeling and histone deacetylase activities. As of 2007, Mi-2/NuRD was the only known protein complex that couples chromatin remodeling ATPase and chromatin deacetylation enzymatic functions.

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.

H3K4me1 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the mono-methylation at the 4th lysine residue of the histone H3 protein and often associated with gene enhancers.

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.

The INO80 subfamily of chromatin remodeling complexes are ATPases, and includes the INO80 and SWR1 complexes.

Chromodomain helicase DNA-binding (CHD) proteins is a subfamily of ATP-dependent chromatin remodeling complexes (remodelers). All remodelers fall under the umbrella of RNA/DNA helicase superfamily 2. In yeast, CHD complexes are primarily responsible for nucleosome assembly and organization. These complexes play an additional role in multicellular eukaryotes, assisting in chromatin access and nucleosome editing.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000153922 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000023852 - 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. ↑ Delmas V, Stokes DG, Perry RP (March 1993). "A mammalian DNA-binding protein that contains a chromodomain and an SNF2/SWI2-like helicase domain". Proceedings of the National Academy of Sciences of the United States of America. 90 (6): 2414–8. Bibcode:1993PNAS...90.2414D. doi: 10.1073/pnas.90.6.2414 . PMC   46097 . PMID   8460153.
  6. ↑ Woodage T, Basrai MA, Baxevanis AD, Hieter P, Collins FS (October 1997). "Characterization of the CHD family of proteins". Proceedings of the National Academy of Sciences of the United States of America. 94 (21): 11472–7. Bibcode:1997PNAS...9411472W. doi: 10.1073/pnas.94.21.11472 . PMC   23509 . PMID   9326634.
  7. ↑ "Entrez Gene: CHD1 chromodomain helicase DNA binding protein 1".
  8. 1 2 3 Clapier CR, Iwasa J, Cairns BR, Peterson CL (July 2017). "Mechanisms of action and regulation of ATP-dependent chromatin-remodelling complexes". Nature Reviews. Molecular Cell Biology. 18 (7): 407–422. doi:10.1038/nrm.2017.26. PMC   8127953 . PMID   28512350.
  9. 1 2 Farnung L, Vos SM, Wigge C, Cramer P (October 2017). "Nucleosome-Chd1 structure and implications for chromatin remodelling". Nature. 550 (7677): 539–542. Bibcode:2017Natur.550..539F. doi:10.1038/nature24046. PMC   5697743 . PMID   29019976.
  10. ↑ Hauk G, McKnight JN, Nodelman IM, Bowman GD (September 2010). "The chromodomains of the Chd1 chromatin remodeler regulate DNA access to the ATPase motor". Molecular Cell. 39 (5): 711–23. doi:10.1016/j.molcel.2010.08.012. PMC   2950701 . PMID   20832723.
  11. 1 2 3 Flanagan JF, Blus BJ, Kim D, Clines KL, Rastinejad F, Khorasanizadeh S (June 2007). "Molecular implications of evolutionary differences in CHD double chromodomains". Journal of Molecular Biology. 369 (2): 334–42. doi:10.1016/j.jmb.2007.03.024. PMC   1948097 . PMID   17433364.
  12. ↑ Cheng W, Su Y, Xu F (December 2013). "CHD1L: a novel oncogene". Molecular Cancer. 12 (1): 170. doi: 10.1186/1476-4598-12-170 . PMC   3931672 . PMID   24359616.
  13. ↑ "CHD1_HUMAN (O14646)". InterPro. European Molecular Biology Laboratory.
  14. ↑ Gaspar-Maia A, Alajem A, Polesso F, Sridharan R, Mason MJ, Heidersbach A, et al. (August 2009). "Chd1 regulates open chromatin and pluripotency of embryonic stem cells". Nature. 460 (7257): 863–8. Bibcode:2009Natur.460..863G. doi:10.1038/nature08212. PMC   3891576 . PMID   19587682.
  15. ↑ Lee Y, Park D, Iyer VR (July 2017). "The ATP-dependent chromatin remodeler Chd1 is recruited by transcription elongation factors and maintains H3K4me3/H3K36me3 domains at actively transcribed and spliced genes". Nucleic Acids Research. 45 (12): 7180–7190. doi:10.1093/nar/gkx321. PMC   5499586 . PMID   28460001.
  16. ↑ Baumgart SJ, Najafova Z, Hossan T, Xie W, Nagarajan S, Kari V, et al. (July 2017). "CHD1 regulates cell fate determination by activation of differentiation-induced genes". Nucleic Acids Research. 45 (13): 7722–7735. doi:10.1093/nar/gkx377. PMC   5570082 . PMID   28475736.
  17. ↑ Gnugnoli, M; Casari, E; Longhese, MP (September 2021). "The chromatin remodeler Chd1 supports MRX and Exo1 functions in resection of DNA double-strand breaks". PLOS Genetics. 17 (9): e1009807. doi: 10.1371/journal.pgen.1009807 . PMC   8462745 . PMID   34520455.
  18. ↑ Kari, V; Mansour, WY; Raul, SK; Baumgart, SJ; Mund, A; Grade, M; Sirma, H; Simon, R; Will, H; Dobbelstein, M; Dikomey, E; Johnsen, SA (November 2016). "Loss of CHD1 causes DNA repair defects and enhances prostate cancer therapeutic responsiveness". EMBO Reports. 17 (11): 1609–1623. doi:10.15252/embr.201642352. PMC   5090703 . PMID   27596623.
  19. ↑ Flanagan JF, Mi LZ, Chruszcz M, Cymborowski M, Clines KL, Kim Y, et al. (December 2005). "Double chromodomains cooperate to recognize the methylated histone H3 tail". Nature. 438 (7071): 1181–5. Bibcode:2005Natur.438.1181F. doi:10.1038/nature04290. PMID   16372014. S2CID   4401500.
  20. ↑ Simic R, Lindstrom DL, Tran HG, Roinick KL, Costa PJ, Johnson AD, et al. (April 2003). "Chromatin remodeling protein Chd1 interacts with transcription elongation factors and localizes to transcribed genes". The EMBO Journal. 22 (8): 1846–56. doi:10.1093/emboj/cdg179. PMC   154471 . PMID   12682017.
  21. ↑ Tai HH, Geisterfer M, Bell JC, Moniwa M, Davie JR, Boucher L, McBurney MW (August 2003). "CHD1 associates with NCoR and histone deacetylase as well as with RNA splicing proteins". Biochemical and Biophysical Research Communications. 308 (1): 170–6. doi:10.1016/S0006-291X(03)01354-8. PMID   12890497.
  22. 1 2 Zhao D, Lu X, Wang G, Lan Z, Liao W, Li J, et al. (February 2017). "Synthetic essentiality of chromatin remodelling factor CHD1 in PTEN-deficient cancer". Nature. 542 (7642): 484–488. Bibcode:2017Natur.542..484Z. doi:10.1038/nature21357. PMC   5448706 . PMID   28166537.
  23. ↑ Huang S, Gulzar ZG, Salari K, Lapointe J, Brooks JD, Pollack JR (September 2012). "Recurrent deletion of CHD1 in prostate cancer with relevance to cell invasiveness". Oncogene. 31 (37): 4164–70. doi:10.1038/onc.2011.590. PMC   5512870 . PMID   22179824.
  24. ↑ Augello MA, Liu D, Deonarine LD, Robinson BD, Huang D, Stelloo S, et al. (April 2019). "CHD1 Loss Alters AR Binding at Lineage-Specific Enhancers and Modulates Distinct Transcriptional Programs to Drive Prostate Tumorigenesis". Cancer Cell. 35 (4): 603–617.e8. doi:10.1016/j.ccell.2019.03.001. PMC   6467783 . PMID   30930119.

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