CHD1

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]

CHD1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCHD1, chromodomain helicase DNA binding protein 1, PILBOS, CHD-1
External IDsOMIM: 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 MbChr 17: 15.93 – 15.99 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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).

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.

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]

References
  1. GRCh38: Ensembl release 89: ENSG00000153922 - Ensembl, May 2017
  2. 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. 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. 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. 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. 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.

Further reading
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