chromatin structure remodeling (RSC) complex

{{short description|ATP-dependent chromatin-remodeling protein complex in yeast}}

RSC (Remodeling the Structure of Chromatin) is a protein complex of the ATP-dependent chromatin remodeler family. The activity of the RSC complex allows for chromatin to be remodeled by altering the structure of the nucleosome.

There are four subfamilies of chromatin remodelers: SWI/SNF, INO80, ISW1, and CHD.{{cite journal | vauthors = Clapier CR, Iwasa J, Cairns BR, Peterson CL | title = Mechanisms of action and regulation of ATP-dependent chromatin-remodelling complexes | journal = Nature Reviews. Molecular Cell Biology | volume = 18 | issue = 7 | pages = 407–422 | date = July 2017 | pmid = 28512350 | doi = 10.1038/nrm.2017.26 | pmc = 8127953 }} The RSC complex is a 15-subunit protein complex first discovered in Saccharomyces cerevisiae in 1996, and is homologous to the SWI/SNF complex found in humans.{{cite journal | vauthors = Cairns BR, Lorch Y, Li Y, Zhang M, Lacomis L, Erdjument-Bromage H, Tempst P, Du J, Laurent B, Kornberg RD | display-authors = 6 | title = RSC, an essential, abundant chromatin-remodeling complex | journal = Cell | volume = 87 | issue = 7 | pages = 1249–60 | date = December 1996 | pmid = 8980231 | doi = 10.1016/S0092-8674(00)81820-6 | doi-access = free }} The RSC complex has ATPase activity in the presence of DNA.

RSC vs. SWI/SNF

While RSC and SWI/SNF have similar structures and functions, RSC is significantly more common than the SWI/SNF complex in yeast, and RSC is required for mitotic cell division. Absence of the RSC complex is lethal; without it, cells cannot survive. RSC consists of a complex of 15 protein subunits, and at least three of these subunits are conserved between RSC and SWI/SNF. RSC and SWI/SNF are composed of very similar components, such as the Sth1 components in RSC and the SWI2/Snf2p in SWI/SNF. Both of these components are ATPases that consist of Arp7 and Arp9, proteins similar to actin.{{cite journal | vauthors = Tang L, Nogales E, Ciferri C | title = Structure and function of SWI/SNF chromatin remodeling complexes and mechanistic implications for transcription | journal = Progress in Biophysics and Molecular Biology | volume = 102 | issue = 2–3 | pages = 122–8 | date = June 2010 | pmid = 20493208 | pmc = 2924208 | doi = 10.1016/j.pbiomolbio.2010.05.001 }} The subunits of Sth1 (Rsc6p, Rsc8p, and Sfh1p) are paralogues to the three subunits of SWI/SNF (Swp73p, Swi3p, and Snf5p). While there are many similarities between these two chromatin remodeling complexes, they remodel different parts of chromatin. They also have opposing roles, specifically when interacting with the PHO8 promoter. RSC works to guarantee the placement of nucleosome N-3, while SWI/SNF attempts to override the placement of N-3.{{cite journal | vauthors = Smith CL, Horowitz-Scherer R, Flanagan JF, Woodcock CL, Peterson CL | title = Structural analysis of the yeast SWI/SNF chromatin remodeling complex | journal = Nature Structural Biology | volume = 10 | issue = 2 | pages = 141–5 | date = February 2003 | pmid = 12524530 | doi = 10.1038/nsb888 }}

RSC and SWI/SNF complexes both function as chromatin remodeling complexes in humans (Homo sapiens) and the common fruit fly (Drosophila melanogaster). SWI/SNF was first discovered when a genetic screen was done in yeast with a mutation causing a deficiency in mating-type switching (swi) and a mutation causing a deficiency in sucrose fermentation. After this chromatin remodeling complex was discovered, the RSC complex was found when its components, Snf2 and Swi2p, were discovered to be homologous to the SWI/SNF complex.

BLAST homology alignment of reference genomes has revealed that the yeast RSC complex is even more similar to the human SWI/SNF complex than it is to yeast's own SWI/SNF complex.

The role of RSC

The role of nucleosomes is a very important topic of study in modern epigenetics research. It is known that nucleosomes interfere with the binding of transcription factors to DNA, therefore allowing them some form of subtle control over the probability of transcription and replication occurring at a given locus. With the help of an in vitro experiment using yeast, it was discovered that RSC is required for nucleosome remodeling. There is evidence that RSC does not remodel the nucleosomes on its own; it uses information from enzymes to help position nucleosomes.

The ATPase activity of the RSC complex is activated by single-stranded, double-stranded, and/or nucleosomal DNA, while some of the other chromatin remodeling complexes are only stimulated by one of these DNA-types.

The RSC complex (specifically Rsc8 and Rsc30) is crucial when fixing double-stranded breaks via non-homologous end joining (NHEJ) in yeast.{{cite journal | vauthors = Shim EY, Ma JL, Oum JH, Yanez Y, Lee SE | title = The yeast chromatin remodeler RSC complex facilitates end joining repair of DNA double-strand breaks | journal = Molecular and Cellular Biology | volume = 25 | issue = 10 | pages = 3934–44 | date = May 2005 | pmid = 15870268 | pmc = 1087737 | doi = 10.1128/mcb.25.10.3934-3944.2005 }} This repair mechanism is important for cell survival as well as for maintaining an organism's genome. These double-stranded breaks are typically caused by radiation, and they can be detrimental to the genome. The breaks can lead to mutations that reposition a chromosome and can even lead to the entire loss of a chromosome. The mutations associated with double-stranded breaks have been linked to cancer and other deadly genetic diseases. RSC not only repairs double-stranded breaks by NHEJ, it also repairs these breaks using homologous recombination with the help of the SWI/SNF complex.{{cite journal | vauthors = Chai B, Huang J, Cairns BR, Laurent BC | title = Distinct roles for the RSC and Swi/Snf ATP-dependent chromatin remodelers in DNA double-strand break repair | journal = Genes & Development | volume = 19 | issue = 14 | pages = 1656–61 | date = July 2005 | pmid = 16024655 | doi = 10.1101/gad.1273105 | pmc = 1176001 }} SWI/SNF is recruited first, prior to two homologous chromosomes bind, and then RSC is recruited to help complete the repair.

Mechanism of action in dsDNA

A single-molecule study using magnetic tweezers and linear DNA observed that RSC generates DNA loops in vitro while simultaneously generating negative supercoils in the template.{{cite journal | vauthors = Lia G, Praly E, Ferreira H, Stockdale C, Tse-Dinh YC, Dunlap D, Croquette V, Bensimon D, Owen-Hughes T | display-authors = 6 | title = Direct observation of DNA distortion by the RSC complex | journal = Molecular Cell | volume = 21 | issue = 3 | pages = 417–25 | date = February 2006 | pmid = 16455496 | pmc = 3443744 | doi = 10.1016/j.molcel.2005.12.013 }} These loops can consist of hundreds of base pairs, but the length depends on how tightly the DNA is wound, as well as how much ATP is present during this translocation. Not only could RSC generate loops, but it was also able to relax these loops, meaning that the translocation of RSC is reversible.

Hydrolysis of ATP allows the complex to translocate the DNA into a loop. RSC can release the loop either by translocating back to the original state at a comparable velocity, or by losing one of its two contacts.

RSC components

The following is a list of RSC components that have been identified in yeast, their corresponding human orthologs, and their functions:

class="wikitable"
Yeast

! Human

! Function

{{Yeast Gene|RSC1}}

| BAF180

| DNA repair mechanisms, tumor suppressor protein {{cite journal | vauthors = Hopson S, Thompson MJ | title = BAF180: Its Roles in DNA Repair and Consequences in Cancer | journal = ACS Chemical Biology | volume = 12 | issue = 10 | pages = 2482–2490 | date = October 2017 | pmid = 28921948 | doi = 10.1021/acschembio.7b00541 }}

{{Yeast Gene|RSC2}}

| BAF180

| DNA repair mechanisms, tumor suppressor protein

{{Yeast Gene|RSC4}}

| BAF180

| DNA repair mechanisms, tumor suppressor protein

{{Yeast Gene|RSC6}}

| BAF60a

|Mitotic growth{{Cite web|url=https://www.yeastgenome.org/locus/S000000648|title=RSC6 {{!}} SGD|website=www.yeastgenome.org|access-date=2020-03-31}}

{{Yeast Gene|RSC8}}

| BAF170, BAF155

| Regulates cortical size/thickness,{{cite journal | vauthors = Tuoc TC, Boretius S, Sansom SN, Pitulescu ME, Frahm J, Livesey FJ, Stoykova A | title = Chromatin regulation by BAF170 controls cerebral cortical size and thickness | journal = Developmental Cell | volume = 25 | issue = 3 | pages = 256–69 | date = May 2013 | pmid = 23643363 | doi = 10.1016/j.devcel.2013.04.005 | doi-access = free | hdl = 11858/00-001M-0000-0013-F327-3 | hdl-access = free }} tumor suppressor {{cite journal | vauthors = DelBove J, Rosson G, Strobeck M, Chen J, Archer TK, Wang W, Knudsen ES, Weissman BE | display-authors = 6 | title = Identification of a core member of the SWI/SNF complex, BAF155/SMARCC1, as a human tumor suppressor gene | journal = Epigenetics | volume = 6 | issue = 12 | pages = 1444–53 | date = December 2011 | pmid = 22139574 | pmc = 3256333 | doi = 10.4161/epi.6.12.18492 }}

See also

References

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{{Transcription coregulators}}