ATP chromatin remodelling

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Cells have multiple remodelling complexes, most of which are multisubunit complexes. Remodelling complexes are grouped into 4 families; INO80, SWI/SNF, CHD and ISWI[1][2]. Although the different families 'slide, evict and edit'[3] nucleosomes, ATP hydrolysis drives DNA translocation of the motor domains of these complexes.

ATP depedant chromatin remodelling involves:

The first complex isolated was SWI/SNF in yeast[4], with the catalytic subunit being identified as SNF2.

In humans, 3 homologues of SWI/SNF proteins have been identified; hbrm and BRG1, which are homologous of SNF2/SWI2 and hSNF5, which is a homologue of SNF5[5]. Hbrm and BRG1 promote transcriptional activation via the glucocorticoid and retonic acid receptors[6]. BRG1 has been found to activate or repress nuclear processes (transcription, elongation, DNA replication), using various mechanisms including being assembled with transcriptional promoters and histone-modifying enzyme complexes[7].

As SWI/SNF plays a key role in the cell cycle, it has been indicated to be a potent tumour suppressor. Mutations within subunits of these complexes have been linked to more than 20% of human cancers[8]. "The cancers with the highest SWI/SNF mutation rates were ovarian clear cell carcinoma (75%), clear cell renal cell carcinoma (57%), hepatocellular carcinoma (40%), gastric cancer (36%), melanoma (34%), and pancreatic cancer (26%)"[9]. Common mutations within the subunits found to lead to cancer include epigenic silencing, rearrangement and deletions which lead to inactivation of SWI/SNF subunit(s)[10].

ATP dependant complexes work synergestically with HAT complexes; as HAT and ATP-dependant complexes are commonly recruited to the same promoters[11], which results in a cascade of reactions leading to enhanced production of the pre-initiation complex.

References

  1. Trotter KW, Archer TK. The BRG1 transcriptional coregulator. Nuclear Receptor Signaling. 2008;6(1).
  2. S. Eustermann, K.Schall, D.Kostrewa, K. Lakomek, M. Strauss, M. Moldt, K-P. Hopfner. Structural Basis for nucleosome remodelling by the INO80 complex. Nature 2018; 556(7701).
  3. S. Eustermann, K.Schall, D.Kostrewa, K. Lakomek, M. Strauss, M. Moldt, K-P. Hopfner. Structural Basis for nucleosome remodelling by the INO80 complex. Nature 2018; 556(7701).
  4. S.Whitehall. CMB2001, lecture 4. 2018.
  5. Muchardt C, Reyes JC, Bourachot B, Leguoy E, Yaniv M. The hbrm and BRG-1 proteins, components of the human SNF/SWI complex, are phosphorylated and excluded from the condensed chromosomes during mitosis. The EMBO Journal. 1996;15(13):3394–402.
  6. Muchardt C, Reyes JC, Bourachot B, Leguoy E, Yaniv M. The hbrm and BRG-1 proteins, components of the human SNF/SWI complex, are phosphorylated and excluded from the condensed chromosomes during mitosis. The EMBO Journal. 1996;15(13):3394–402.
  7. Trotter KW, Archer TK. The BRG1 transcriptional coregulator. Nuclear Receptor Signaling. 2008;6(1).
  8. S.Whitehall. CMB2001, Lecture 4. 2018
  9. Shain AH, Pollack JR. The Spectrum of SWI/SNF Mutations, Ubiquitous in Human Cancers. PLoS ONE. 2013;8(1)
  10. Shain AH, Pollack JR. The Spectrum of SWI/SNF Mutations, Ubiquitous in Human Cancers. PLoS ONE. 2013;8(1).
  11. S.WHitehall. CMB2001, lecture 4. 2018.
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