Chromatin structure remodeling (RSC) complex

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RSC (Remodeling the Structure of Chromatin) is a member 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. [1]

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There are four subfamilies of chromatin remodelers: SWI/SNF, INO80, ISW1, and CHD. [2] The RSC complex is a 15-subunit chromatin remodeling complex initially found in Saccharomyces cerevisiae , and is homologous to the SWI/SNF complex found in humans. [1] The RSC complex has ATPase activity in the presence of DNA. [1]

RSC Complex vs. SWI/SNF

While RSC and SWI/SNF are considered homologous, RSC is significantly more common than the SWI/SNF complex and it is required for mitotic cell division. [1] Without the RSC complex, cells would not survive. [1] RSC consists of 15 subunits, and at least three of these subunits are conserved between RSC and SWI/SNF. [1] 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, which are proteins that are similar to actin. [3] 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. [3] 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. [4]

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. [1] 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.

Due to research done using BLAST (biotechnology), it is believed that the yeast RSC complex is even more similar to the human SWI/SNF complex than it is to the yeast SWI/SNF complex. [1]

The Role of RSC

The role of nucleosomes is a very important topic of research. It is known that nucleosomes interfere with the binding of transcription factors to DNA, therefore they can control transcription and replication. 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. [1]

The RSC complex (specifically Rsc8 and Rsc30) is crucial when fixing double-stranded breaks via non-homologous end joining (NHEJ) in yeast. [5] This repair mechanism is important for cell survival, as well 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. [5] RSC does not only repair double-stranded breaks by NHEJ, it also repairs this breaks using homologous recombination with the help of the SWI/SNF complex. [6] SWI/SNF is recruited first, prior to two homologous chromosomes bind, and then RSC is recruited to help complete the repair. [6]

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. [7] 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. [7] Not only could RSC generate loops, but it was also able to relax these loops, meaning that the translocation of RSC is reversible. [7]

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. [7]

RSC components

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

YeastHumanFunction
RSC1 BAF180DNA repair mechanisms, tumor suppressor protein [8]
RSC2 BAF180DNA repair mechanisms, tumor suppressor protein [8]
RSC4 BAF180DNA repair mechanisms, tumor suppressor protein [8]
RSC6 BAF60a Mitotic growth [9]
RSC8 BAF170, BAF155Regulates cortical size/thickness, [10] tumor suppressor [11]

See also

Related Research Articles

<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">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.

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">SMARCA4</span> Protein-coding gene in the species Homo sapiens

Transcription activator BRG1 also known as ATP-dependent chromatin remodeler SMARCA4 is a protein that in humans is encoded by the SMARCA4 gene.

<span class="mw-page-title-main">SMARCA2</span> Protein-coding gene in the species Homo sapiens

Probable global transcription activator SNF2L2 is a protein that in humans is encoded by the SMARCA2 gene.

<span class="mw-page-title-main">ACTL6A</span> Protein-coding gene in the species Homo sapiens

Actin-like protein 6A is a protein that in humans is encoded by the ACTL6A gene.

<span class="mw-page-title-main">ARID1A</span> Protein-coding gene in humans

AT-rich interactive domain-containing protein 1A is a protein that in humans is encoded by the ARID1A gene.

<span class="mw-page-title-main">SMARCE1</span> Protein-coding gene in the species Homo sapiens

SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E member 1 is a protein that in humans is encoded by the SMARCE1 gene.

<span class="mw-page-title-main">SMARCC2</span> Protein-coding gene in the species Homo sapiens

SWI/SNF complex subunit SMARCC2 is a protein that in humans is encoded by the SMARCC2 gene.

<span class="mw-page-title-main">ARID1B</span> Protein-coding gene in humans

AT-rich interactive domain-containing protein 1B is a protein that in humans is encoded by the ARID1B gene. ARID1B is a component of the human SWI/SNF chromatin remodeling complex.

<span class="mw-page-title-main">SMARCD1</span> Protein-coding gene in the species Homo sapiens

SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1 is a protein that in humans is encoded by the SMARCD1 gene.

<span class="mw-page-title-main">CHD1</span> Chromatin remodeling protein that is widely conserved across many eukaryotic organisms

The Chromodomain-Helicase DNA-binding 1 is a protein that, in humans, is encoded by the CHD1 gene. 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.

<span class="mw-page-title-main">PBRM1</span> Protein-coding gene in the species Homo sapiens

Protein polybromo-1 (PB1) also known as BRG1-associated factor 180 (BAF180) is a protein that in humans is encoded by the PBRM1 gene.

<span class="mw-page-title-main">SMC5</span> Protein-coding gene in the species Homo sapiens

Structural maintenance of chromosomes protein 5 is a protein encoded by the SMC5 gene in human.

<span class="mw-page-title-main">SMARCD2</span> Protein-coding gene in the species Homo sapiens

SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 2 is a protein that in humans is encoded by the SMARCD2 gene.

ISWI is one of the five major DNA chromatin remodeling complex types, or subfamilies, found in most eukaryotic organisms. ISWI remodeling complexes place nucleosomes along segments of DNA at regular intervals. The placement of nucleosomes by ISWI protein complexes typically results in the silencing of the DNA because the nucleosome placement prevents transcription of the DNA. ISWI, like the closely related SWI/SNF subfamily, is an ATP-dependent chromatin remodeler. However, the chromatin remodeling activities of ISWI and SWI/SNF are distinct and mediate the binding of non-overlapping sets of DNA transcription factors.

Reptin is a tumor repressor protein that is a member of the ATPases Associated with various cellular Activities (AAA+) helicase family and regulates KAI1. Desumoylation of reptin alters the repressive function of reptin and its association with HDAC1. The sumoylation status of reptin modulates the invasive activity of cancer cells with metastatic potential. Reptin was reported in 2010 to be a good marker for metastasis. Another name for reptin, RuvB-like 2 comes from its similarity to RuvB, an ATP-dependent helicase found in bacteria. Reptin is highly conserved, being found in yeast, drosophila, and humans. It presents itself as a member of a number of different protein complexes, most of which function in chromatin modification, including PRC1, TIP60/NuA4 and INO80. Hence, it also has the names INO80J, TIP48, and TIP49B. In the majority of its functions, reptin is paired with a very similar protein, pontin (RUVBL1).

Nucleosome Remodeling Factor (NURF) is an ATP-dependent chromatin remodeling complex first discovered in Drosophila melanogaster that catalyzes nucleosome sliding in order to regulate gene transcription. It contains an ISWI ATPase, making it part of the ISWI family of chromatin remodeling complexes. NURF is highly conserved among eukaryotes and is involved in transcriptional regulation of developmental genes.

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

Robert E. Kingston is an American biochemist who studies the functional and regulatory role nucleosomes play in gene expression, specifically during early development. After receiving his PhD (1981) and completing post-doctoral research, Kingston became an assistant professor at Massachusetts General Hospital (1985), where he started a research laboratory focused on understanding chromatin's structure with regards to transcriptional regulation. As a Harvard graduate himself, Kingston has served his alma mater through his leadership.

References

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  7. 1 2 3 4 Lia G, Praly E, Ferreira H, Stockdale C, Tse-Dinh YC, Dunlap D, et al. (February 2006). "Direct observation of DNA distortion by the RSC complex". Molecular Cell. 21 (3): 417–25. doi:10.1016/j.molcel.2005.12.013. PMC   3443744 . PMID   16455496.
  8. 1 2 3 Hopson S, Thompson MJ (October 2017). "BAF180: Its Roles in DNA Repair and Consequences in Cancer". ACS Chemical Biology. 12 (10): 2482–2490. doi:10.1021/acschembio.7b00541. PMID   28921948.
  9. ↑ "RSC6 | SGD". www.yeastgenome.org. Retrieved 2020-03-31.
  10. ↑ Tuoc TC, Boretius S, Sansom SN, Pitulescu ME, Frahm J, Livesey FJ, Stoykova A (May 2013). "Chromatin regulation by BAF170 controls cerebral cortical size and thickness". Developmental Cell. 25 (3): 256–69. doi: 10.1016/j.devcel.2013.04.005 . hdl: 11858/00-001M-0000-0013-F327-3 . PMID   23643363.
  11. ↑ DelBove J, Rosson G, Strobeck M, Chen J, Archer TK, Wang W, et al. (December 2011). "Identification of a core member of the SWI/SNF complex, BAF155/SMARCC1, as a human tumor suppressor gene". Epigenetics. 6 (12): 1444–53. doi:10.4161/epi.6.12.18492. PMC   3256333 . PMID   22139574.
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