View source for SWI/SNF

{{short description|Subfamily of ATP-dependent chromatin remodeling complexes}}
{{Infobox protein family
| Symbol = Snf2
| Name = Snf2 ATPase bound to a nucleosome
| image = Snf2 ATPase domain in complex with a nucleosome.png
| width =
| caption = Cryo-EM reconstruction of ''S. cerevisiae'' Snf2 ATPase in complex with a nucleosome
| Pfam = PF00176
| Pfam_clan =
| InterPro = IPR000330
| SMART = DEXDc
| PROSITE =
| MEROPS =
| SCOP = 5x0x
| TCDB =
| OPM family =
| OPM protein =
| CAZy =
| CDD =
}}
In [[molecular biology]], '''SWI/SNF''' (SWItch/Sucrose Non-Fermentable),<ref name="pmid6392017">{{cite journal | vauthors = Neigeborn L, Carlson M | title = Genes affecting the regulation of SUC2 gene expression by glucose repression in Saccharomyces cerevisiae | journal = Genetics | volume = 108 | issue = 4 | pages = 845–858 | date = December 1984 | pmid = 6392017 | pmc = 1224269 | doi = 10.1093/genetics/108.4.845 }}</ref><ref name="pmid6436497">{{cite journal |vauthors=Stern M, Jensen R, Herskowitz I |date=October 1984 |title=Five SWI genes are required for expression of the HO gene in yeast |url=https://www.sciencedirect.com/science/article/abs/pii/0022283684903152 |journal=Journal of Molecular Biology |volume=178 |issue=4 |pages=853–868 |doi=10.1016/0022-2836(84)90315-2 |pmid=6436497}}</ref> 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 ({{Yeast Gene|SWI1}}, {{Yeast Gene|SWI2}}/{{Yeast Gene|SNF2}}, {{Yeast Gene|SWI3}}, {{Yeast Gene|SWI5}}, {{Yeast Gene|SWI6}}), as well as other [[polypeptides]].<ref name="pmid9118215">{{cite journal | vauthors = Pazin MJ, Kadonaga JT | title = SWI2/SNF2 and related proteins: ATP-driven motors that disrupt protein-DNA interactions? | journal = Cell | volume = 88 | issue = 6 | pages = 737–740 | date = March 1997 | pmid = 9118215 | doi = 10.1016/S0092-8674(00)81918-2 | doi-access = free }}</ref>  It possesses a DNA-stimulated [[ATPase]] activity that can destabilize [[histone]]-DNA interactions in reconstituted nucleosomes in an [[Adenosine triphosphate|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, enabling binding of specific transcription factors,<ref>{{Cite journal |last1=Barisic |first1=Darko |last2=Stadler |first2=Michael B. |last3=Iurlaro |first3=Mario |last4=Schübeler |first4=Dirk |date=May 2019 |title=Mammalian ISWI and SWI/SNF selectively mediate binding of distinct transcription factors |journal=Nature |language=en |volume=569 |issue=7754 |pages=136–140 |doi=10.1038/s41586-019-1115-5 |issn=1476-4687 |pmc=6522387 |pmid=30996347|bibcode=2019Natur.569..136B }}</ref> and allowing genes to be activated or repressed.<ref name = "Clapier_2017" />
The human analogs of SWI/SNF are "[[SMARCA4|BRG1]]- or [[SMARCA2|BRM]]-associated factors", or BAF (SWI/SNF-A) and "Polybromo-associated BAF", which is also known as PBAF (SWI/SNF-B).<ref name="pmid126655912">{{cite journal | vauthors = Nie Z, Yan Z, Chen EH, Sechi S, Ling C, Zhou S, Xue Y, Yang D, Murray D, Kanakubo E, Cleary ML, Wang W | display-authors = 6 | title = Novel SWI/SNF chromatin-remodeling complexes contain a mixed-lineage leukemia chromosomal translocation partner | journal = Molecular and Cellular Biology | volume = 23 | issue = 8 | pages = 2942–2952 | date = April 2003 | pmid = 12665591 | pmc = 152562 | doi = 10.1128/MCB.23.8.2942-2952.2003 }}</ref> There are also ''[[Drosophila]]'' analogs of SWI/SNF, known as "Brahma Associated Protein", or BAP and "Polybromo-associated BAP", also known as PBAP.<ref name=":0">{{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 = 122–128 | date = June 2010 | pmid = 20493208 | pmc = 2924208 | doi = 10.1016/j.pbiomolbio.2010.05.001 }}</ref>
== Mechanism of action ==
It has been found that the SWI/SNF complex (in yeast) is capable of altering the position of [[nucleosomes]] along [[DNA]].<ref>{{cite journal |vauthors=Hirschhorn JN, Brown SA, Clark CD, Winston F |date=December 1992 |title=Evidence that SNF2/SWI2 and SNF5 activate transcription in yeast by altering chromatin structure |url=https://genesdev.cshlp.org/content/6/12a/2288 |journal=Genes & Development |volume=6 |issue=12A |pages=2288–2298 |doi=10.1101/gad.6.12a.2288 |pmid=1459453|doi-access=free }}</ref><ref name="pmid10466730">{{cite journal |vauthors=Whitehouse I, Flaus A, Cairns BR, White MF, Workman JL, Owen-Hughes T |date=August 1999 |title=Nucleosome mobilization catalysed by the yeast SWI/SNF complex |url=https://www.nature.com/articles/23506 |journal=Nature |volume=400 |issue=6746 |pages=784–787 |bibcode=1999Natur.400..784W |doi=10.1038/23506 |pmid=10466730 |s2cid=2841873}}</ref> These alterations are classified in three different ways, and they are seen as the processes of sliding nucleosomes, ejecting nucleosomes, and ejecting only certain components of the nucleosome.<ref name="Clapier_2017" /> Due to the actions performed by the SWI/SNF subfamily, they are referred to as "access remodellers" and promote gene expression by exposing binding sites so that transcription factors can bind more easily.<ref name="Clapier_2017" /> Two mechanisms for nucleosome remodeling by SWI/SNF have been proposed.<ref name="pmid12897850">{{cite journal |vauthors=van Holde K, Yager T |date=June 2003 |title=Models for chromatin remodeling: a critical comparison |url=https://cdnsciencepub.com/doi/10.1139/o03-038 |journal=Biochemistry and Cell Biology |volume=81 |issue=3 |pages=169–172 |doi=10.1139/o03-038 |pmid=12897850}}</ref>  The first model contends that a unidirectional diffusion of a twist defect within the nucleosomal DNA results in a corkscrew-like propagation of DNA over the octamer surface that initiates at the DNA entry site of the nucleosome.  The other is known as the "bulge" or "loop-recapture" mechanism and it involves the dissociation of DNA at the edge of the nucleosome with re-association of DNA inside the nucleosome, forming a DNA bulge on the octamer surface.  The DNA loop would then propagate across the surface of the [[histone]] octamer in a wave-like manner, resulting in the re-positioning of DNA without changes in the total number of histone-DNA contacts.<ref name="pmid12666181">{{cite journal |vauthors=Flaus A, Owen-Hughes T |date=April 2003 |title=Mechanisms for nucleosome mobilization |url=https://onlinelibrary.wiley.com/doi/10.1002/bip.10323 |journal=Biopolymers |volume=68 |issue=4 |pages=563–578 |doi=10.1002/bip.10323 |pmid=12666181}}</ref> A recent study<ref name="pmid16518397">{{cite journal |vauthors=Zofall M, Persinger J, Kassabov SR, Bartholomew B |date=April 2006 |title=Chromatin remodeling by ISW2 and SWI/SNF requires DNA translocation inside the nucleosome |url=https://www.nature.com/articles/nsmb1071 |journal=Nature Structural & Molecular Biology |volume=13 |issue=4 |pages=339–346 |doi=10.1038/nsmb1071 |pmid=16518397 |s2cid=24163324}}</ref> has provided strong evidence against the twist diffusion mechanism and has further strengthened the loop-recapture model.
== Role as a tumor suppressor ==
The mammalian SWI/SNF (mSWI/SNF) complex functions as a tumor suppressor in many human malignant cancers.<ref>{{cite journal | vauthors = Hodges C, Kirkland JG, Crabtree GR | title = The Many Roles of BAF (mSWI/SNF) and PBAF Complexes in Cancer | journal = Cold Spring Harbor Perspectives in Medicine | volume = 6 | issue = 8 | pages = a026930 | date = August 2016 | pmid = 27413115 | pmc = 4968166 | doi = 10.1101/cshperspect.a026930 }}</ref> Early studies identified that SWI/SNF subunits were frequently absent in cancer cell lines.<ref>{{cite journal | vauthors = Dunaief JL, Strober BE, Guha S, Khavari PA, Alin K, Luban J, Begemann M, Crabtree GR, Goff SP | display-authors = 6 | title = The retinoblastoma protein and BRG1 form a complex and cooperate to induce cell cycle arrest | journal = Cell | volume = 79 | issue = 1 | pages = 119–130 | date = October 1994 | pmid = 7923370 | doi = 10.1016/0092-8674(94)90405-7 | s2cid = 7058539 }}</ref> SWI/SNF was first identified in 1998 as a tumor suppressor in [[rhabdoid tumor]]s, a rare pediatric malignant cancer.<ref name="pmid9671307">{{cite journal | vauthors = Versteege I, Sévenet N, Lange J, Rousseau-Merck MF, Ambros P, Handgretinger R, Aurias A, Delattre O | display-authors = 6 | title = Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer | journal = Nature | volume = 394 | issue = 6689 | pages = 203–206 | date = July 1998 | pmid = 9671307 | doi = 10.1038/28212 | s2cid = 6019090 | bibcode = 1998Natur.394..203V }}</ref> Other instances of SWI/SNF acting as a tumor suppressor comes from the heterozygous deletion of BAF47<ref>{{cite journal | vauthors = Melo JV, Gordon DE, Cross NC, Goldman JM | title = The ABL-BCR fusion gene is expressed in chronic myeloid leukemia | journal = Blood | volume = 81 | issue = 1 | pages = 158–165 | date = January 1993 | pmid = 8417787 | doi = 10.1182/blood.v81.1.158.bloodjournal811158 | doi-access = free }}</ref> or alteration of BAF47.<ref>{{cite journal | vauthors = Yuge M, Nagai H, Uchida T, Murate T, Hayashi Y, Hotta T, Saito H, Kinoshita T | display-authors = 6 | title = HSNF5/INI1 gene mutations in lymphoid malignancy | journal = Cancer Genetics and Cytogenetics | volume = 122 | issue = 1 | pages = 37–42 | date = October 2000 | pmid = 11104031 | doi = 10.1016/s0165-4608(00)00274-0 }}</ref>  These instances result in cases of chronic and acute [[Chronic myelogenous leukemia|CML]] and in rarer cases, [[Hodgkin lymphoma|Hodgkin's lymphoma]], respectively. To prove that BAF47, also known as [[SMARCB1]], acts as a tumor suppressor, experiments resulting in the formation of rhabdoid tumors in mice were conducted via total knockout of BAF47.<ref>{{cite journal | vauthors = Reisman D, Glaros S, Thompson EA | title = The SWI/SNF complex and cancer | journal = Oncogene | volume = 28 | issue = 14 | pages = 1653–1668 | date = April 2009 | pmid = 19234488 | doi = 10.1038/onc.2009.4 | doi-access =  }}</ref> As DNA sequencing costs diminished, many tumors were sequenced for the first time around 2010. Several of these studies revealed SWI/SNF to be a tumor suppressor in a number of diverse malignancies.<ref name="pmid20942669">{{cite journal | vauthors = Wiegand KC, Shah SP, Al-Agha OM, Zhao Y, Tse K, Zeng T, Senz J, McConechy MK, Anglesio MS, Kalloger SE, Yang W, Heravi-Moussavi A, Giuliany R, Chow C, Fee J, Zayed A, Prentice L, Melnyk N, Turashvili G, Delaney AD, Madore J, Yip S, McPherson AW, Ha G, Bell L, Fereday S, Tam A, Galletta L, Tonin PN, Provencher D, Miller D, Jones SJ, Moore RA, Morin GB, Oloumi A, Boyd N, Aparicio SA, Shih I, Mes-Masson AM, Bowtell DD, Hirst M, Gilks B, Marra MA, Huntsman DG | display-authors = 6 | title = ARID1A mutations in endometriosis-associated ovarian carcinomas | journal = The New England Journal of Medicine | volume = 363 | issue = 16 | pages = 1532–1543 | date = October 2010 | pmid = 20942669 | pmc = 2976679 | doi = 10.1056/NEJMoa1008433 }}</ref><ref name="pmid21822264">{{cite journal | vauthors = Li M, Zhao H, Zhang X, Wood LD, Anders RA, Choti MA, Pawlik TM, Daniel HD, Kannangai R, Offerhaus GJ, Velculescu VE, Wang L, Zhou S, Vogelstein B, Hruban RH, Papadopoulos N, Cai J, Torbenson MS, Kinzler KW | display-authors = 6 | title = Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma | journal = Nature Genetics | volume = 43 | issue = 9 | pages = 828–829 | date = August 2011 | pmid = 21822264 | pmc = 3163746 | doi = 10.1038/ng.903 }}</ref><ref name="pmid22233809">{{cite journal | vauthors = Shain AH, Giacomini CP, Matsukuma K, Karikari CA, Bashyam MD, Hidalgo M, Maitra A, Pollack JR | display-authors = 6 | title = Convergent structural alterations define SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeler as a central tumor suppressive complex in pancreatic cancer | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 5 | pages = E252–E259 | date = January 2012 | pmid = 22233809 | pmc = 3277150 | doi = 10.1073/pnas.1114817109 | doi-access = free }}</ref><ref name="pmid21248752">{{cite journal | vauthors = Varela I, Tarpey P, Raine K, Huang D, Ong CK, Stephens P, Davies H, Jones D, Lin ML, Teague J, Bignell G, Butler A, Cho J, Dalgliesh GL, Galappaththige D, Greenman C, Hardy C, Jia M, Latimer C, Lau KW, Marshall J, McLaren S, Menzies A, Mudie L, Stebbings L, Largaespada DA, Wessels LF, Richard S, Kahnoski RJ, Anema J, Tuveson DA, Perez-Mancera PA, Mustonen V, Fischer A, Adams DJ, Rust A, Chan-on W, Subimerb C, Dykema K, Furge K, Campbell PJ, Teh BT, Stratton MR, Futreal PA | display-authors = 6 | title = Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma | journal = Nature | volume = 469 | issue = 7331 | pages = 539–542 | date = January 2011 | pmid = 21248752 | pmc = 3030920 | doi = 10.1038/nature09639 | bibcode = 2011Natur.469..539V }}</ref> Several studies revealed that subunits of the mammalian complex, including ARID1A,<ref>{{cite journal | vauthors = Mathur R, Alver BH, San Roman AK, Wilson BG, Wang X, Agoston AT, Park PJ, Shivdasani RA, Roberts CW | display-authors = 6 | title = ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice | journal = Nature Genetics | volume = 49 | issue = 2 | pages = 296–302 | date = February 2017 | pmid = 27941798 | pmc = 5285448 | doi = 10.1038/ng.3744 }}</ref> PBRM1,<ref name="pmid21248752"/> SMARCB1,<ref>{{cite journal | vauthors = Isakoff MS, Sansam CG, Tamayo P, Subramanian A, Evans JA, Fillmore CM, Wang X, Biegel JA, Pomeroy SL, Mesirov JP, Roberts CW | display-authors = 6 | title = Inactivation of the Snf5 tumor suppressor stimulates cell cycle progression and cooperates with p53 loss in oncogenic transformation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 49 | pages = 17745–17750 | date = December 2005 | pmid = 16301525 | pmc = 1308926 | doi = 10.1073/pnas.0509014102 | doi-access = free | bibcode = 2005PNAS..10217745I }}</ref> SMARCA4,<ref name="Hodges_2018">{{cite journal | vauthors = Hodges HC, Stanton BZ, Cermakova K, Chang CY, Miller EL, Kirkland JG, Ku WL, Veverka V, Zhao K, Crabtree GR | display-authors = 6 | title = Dominant-negative SMARCA4 mutants alter the accessibility landscape of tissue-unrestricted enhancers | journal = Nature Structural & Molecular Biology | volume = 25 | issue = 1 | pages = 61–72 | date = January 2018 | pmid = 29323272 | pmc = 5909405 | doi = 10.1038/s41594-017-0007-3 }}</ref> and ARID2,<ref name="pmid21822264"/> are frequently mutated in human cancers. It has been noted that total loss of BAF47 is extremely rare and instead, most cases of tumors that resulted from SWI/SNF subunits come from BRG1 deletion, BRM deletion, or total loss of both subunits.<ref>{{cite journal | vauthors = Muchardt C, Yaniv M | title = When the SWI/SNF complex remodels...the cell cycle | journal = Oncogene | volume = 20 | issue = 24 | pages = 3067–3075 | date = May 2001 | pmid = 11420722 | doi = 10.1038/sj.onc.1204331 | doi-access =  }}</ref> Further analysis concluded that total loss of both subunits was present in about 10% of tumor cell lines after 100 cell lines were looked at.<ref>{{cite journal | vauthors = Decristofaro MF, Betz BL, Rorie CJ, Reisman DN, Wang W, Weissman BE | title = Characterization of SWI/SNF protein expression in human breast cancer cell lines and other malignancies | journal = Journal of Cellular Physiology | volume = 186 | issue = 1 | pages = 136–145 | date = January 2001 | pmid = 11147808 | doi = 10.1002/1097-4652(200101)186:1<136::aid-jcp1010>3.0.co;2-4 | s2cid = 25016283 }}</ref> A meta-analysis of many sequencing studies demonstrated SWI/SNF to be mutated in approximately 20% of human malignancies.<ref name="pmid23355908">{{cite journal | vauthors = Shain AH, Pollack JR | title = The spectrum of SWI/SNF mutations, ubiquitous in human cancers | journal = PLOS ONE | volume = 8 | issue = 1 | pages = e55119 | year = 2013 | pmid = 23355908 | pmc = 3552954 | doi = 10.1371/journal.pone.0055119 | doi-access = free | bibcode = 2013PLoSO...855119S }}</ref>
== Role as a cancer dependency ==
The function of the mammalian SWI/SNF complex is highly tissue-specific,<ref>{{Cite journal |last1=Alver |first1=Burak H. |last2=Kim |first2=Kimberly H. |last3=Lu |first3=Ping |last4=Wang |first4=Xiaofeng |last5=Manchester |first5=Haley E. |last6=Wang |first6=Weishan |last7=Haswell |first7=Jeffrey R. |last8=Park |first8=Peter J. |last9=Roberts |first9=Charles W. M. |date=2017-03-06 |title=The SWI/SNF chromatin remodelling complex is required for maintenance of lineage specific enhancers |journal=Nature Communications |volume=8 |pages=14648 |doi=10.1038/ncomms14648 |issn=2041-1723 |pmc=5343482 |pmid=28262751|bibcode=2017NatCo...814648A }}</ref> and in addition to its role as a tumor suppressor described above, SWI/SNF complexes also act as dependencies in several different cancer contexts, including [[acute myeloid leukemia]],<ref name=":1">{{Cite journal |last1=Chambers |first1=Courtney |last2=Cermakova |first2=Katerina |last3=Chan |first3=Yuen San |last4=Kurtz |first4=Kristen |last5=Wohlan |first5=Katharina |last6=Lewis |first6=Andrew Henry |last7=Wang |first7=Christiana |last8=Pham |first8=Anh |last9=Dejmek |first9=Milan |last10=Sala |first10=Michal |last11=Loeza Cabrera |first11=Mario |last12=Aguilar |first12=Rogelio |last13=Nencka |first13=Radim |last14=Lacorazza |first14=Daniel |last15=Rau |first15=Rachel E. |date=2023-01-20 |title=SWI/SNF blockade disrupts PU.1-directed enhancer programs in normal hematopoietic cells and acute myeloid leukemia |journal=Cancer Research |volume=83 |issue=7 |pages=CAN–22–2129 |doi=10.1158/0008-5472.CAN-22-2129 |issn=1538-7445 |pmid=36662812|pmc=10071820 |s2cid=256031128 }}</ref><ref>{{Cite journal |last1=Rago |first1=Florencia |last2=Rodrigues |first2=Lindsey Ulkus |last3=Bonney |first3=Megan |last4=Sprouffske |first4=Kathleen |last5=Kurth |first5=Esther |last6=Elliott |first6=GiNell |last7=Ambrose |first7=Jessi |last8=Aspesi |first8=Peter |last9=Oborski |first9=Justin |last10=Chen |first10=Julie T. |last11=McDonald |first11=E. Robert |last12=Mapa |first12=Felipa A. |last13=Ruddy |first13=David A. |last14=Kauffmann |first14=Audrey |last15=Abrams |first15=Tinya |date=2022-03-01 |title=Exquisite Sensitivity to Dual BRG1/BRM ATPase Inhibitors Reveals Broad SWI/SNF Dependencies in Acute Myeloid Leukemia |journal=Molecular Cancer Research |volume=20 |issue=3 |pages=361–372 |doi=10.1158/1541-7786.MCR-21-0390 |issn=1557-3125 |pmid=34799403|s2cid=244454472 |doi-access=free }}</ref> [[prostate cancer]],<ref name=":2">{{Cite journal |last1=Xiao |first1=Lanbo |last2=Parolia |first2=Abhijit |last3=Qiao |first3=Yuanyuan |last4=Bawa |first4=Pushpinder |last5=Eyunni |first5=Sanjana |last6=Mannan |first6=Rahul |last7=Carson |first7=Sandra E. |last8=Chang |first8=Yu |last9=Wang |first9=Xiaoju |last10=Zhang |first10=Yuping |last11=Vo |first11=Josh N. |last12=Kregel |first12=Steven |last13=Simko |first13=Stephanie A. |last14=Delekta |first14=Andrew D. |last15=Jaber |first15=Mustapha |date=January 2022 |title=Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer |journal=Nature |volume=601 |issue=7893 |pages=434–439 |doi=10.1038/s41586-021-04246-z |issn=1476-4687 |pmc=8770127 |pmid=34937944|bibcode=2022Natur.601..434X }}</ref> [[neuroblastoma]],<ref name=":5" /> [[uveal melanoma]],<ref>{{Cite journal |last1=Rago |first1=Florencia |last2=Elliott |first2=GiNell |last3=Li |first3=Ailing |last4=Sprouffske |first4=Kathleen |last5=Kerr |first5=Grainne |last6=Desplat |first6=Aurore |last7=Abramowski |first7=Dorothee |last8=Chen |first8=Julie T. |last9=Farsidjani |first9=Ali |last10=Xiang |first10=Kay X. |last11=Bushold |first11=Geoffrey |last12=Feng |first12=Yun |last13=Shirley |first13=Matthew D. |last14=Bric |first14=Anka |last15=Vattay |first15=Anthony |date=October 2020 |title=The Discovery of SWI/SNF Chromatin Remodeling Activity as a Novel and Targetable Dependency in Uveal Melanoma |url=https://pubmed.ncbi.nlm.nih.gov/32747420 |journal=Molecular Cancer Therapeutics |volume=19 |issue=10 |pages=2186–2195 |doi=10.1158/1535-7163.MCT-19-1013 |issn=1538-8514 |pmid=32747420|s2cid=222093985 }}</ref> [[synovial sarcoma]],<ref>{{Cite journal |last1=Brien |first1=Gerard L. |last2=Remillard |first2=David |last3=Shi |first3=Junwei |last4=Hemming |first4=Matthew L. |last5=Chabon |first5=Jonathon |last6=Wynne |first6=Kieran |last7=Dillon |first7=Eugène T. |last8=Cagney |first8=Gerard |last9=Van Mierlo |first9=Guido |last10=Baltissen |first10=Marijke P. |last11=Vermeulen |first11=Michiel |last12=Qi |first12=Jun |last13=Fröhling |first13=Stefan |last14=Gray |first14=Nathanael S. |last15=Bradner |first15=James E. |date=2018-11-15 |title=Targeted degradation of BRD9 reverses oncogenic gene expression in synovial sarcoma |journal=eLife |volume=7 |pages=e41305 |doi=10.7554/eLife.41305 |issn=2050-084X |pmc=6277197 |pmid=30431433 |doi-access=free }}</ref> and lung cancer.<ref>{{Cite journal |last=Trejo-Villegas |first=Octavio A. |last2=Irene |first2=Heijink H. |last3=Federico |first3=Ávila-Moreno |date=2024-06-22 |title=Preclinical Evidence in the Assembly of Mammalian SWI/SNF Complexes: Epigenetic Insights and Clinical Perspectives in Human Lung Diseases Therapy |url=https://doi.org/10.1016/j.ymthe.2024.06.026 |journal=Molecular Therapy |doi=10.1016/j.ymthe.2024.06.026 |issn=1525-0016}}</ref> Because SWI/SNF complexes are viewed as potentially viable drug targets for treating tumors that depend of SWI/SNF activity,<ref>{{Cite journal |last1=Hohmann |first1=Anja F. |last2=Vakoc |first2=Christopher R. |date=August 2014 |title=A rationale to target the SWI/SNF complex for cancer therapy |journal=Trends in Genetics |volume=30 |issue=8 |pages=356–363 |doi=10.1016/j.tig.2014.05.001 |issn=0168-9525 |pmc=4112150 |pmid=24932742}}</ref> several programs in the pharmaceutical industry<ref name=":3">{{Cite journal |last1=Papillon |first1=Julien P. N. |last2=Nakajima |first2=Katsumasa |last3=Adair |first3=Christopher D. |last4=Hempel |first4=Jonathan |last5=Jouk |first5=Andriana O. |last6=Karki |first6=Rajeshri G. |last7=Mathieu |first7=Simon |last8=Möbitz |first8=Henrik |last9=Ntaganda |first9=Rukundo |last10=Smith |first10=Troy |last11=Visser |first11=Michael |last12=Hill |first12=Susan E. |last13=Hurtado |first13=Felipe Kellermann |last14=Chenail |first14=Gregg |last15=Bhang |first15=Hyo-Eun C. |date=2018-11-21 |title=Discovery of Orally Active Inhibitors of Brahma Homolog (BRM)/SMARCA2 ATPase Activity for the Treatment of Brahma Related Gene 1 (BRG1)/SMARCA4-Mutant Cancers |url=https://pubmed.ncbi.nlm.nih.gov/30339381 |journal=Journal of Medicinal Chemistry |volume=61 |issue=22 |pages=10155–10172 |doi=10.1021/acs.jmedchem.8b01318 |issn=1520-4804 |pmid=30339381|s2cid=53010943 }}</ref><ref name=":4">{{Cite journal |last1=Cantley |first1=Jennifer |last2=Ye |first2=Xiaofen |last3=Rousseau |first3=Emma |last4=Januario |first4=Tom |last5=Hamman |first5=Brian D. |last6=Rose |first6=Christopher M. |last7=Cheung |first7=Tommy K. |last8=Hinkle |first8=Trent |last9=Soto |first9=Leofal |last10=Quinn |first10=Connor |last11=Harbin |first11=Alicia |last12=Bortolon |first12=Elizabeth |last13=Chen |first13=Xin |last14=Haskell |first14=Roy |last15=Lin |first15=Eva |date=2022-11-10 |title=Selective PROTAC-mediated degradation of SMARCA2 is efficacious in SMARCA4 mutant cancers |journal=Nature Communications |volume=13 |issue=1 |pages=6814 |doi=10.1038/s41467-022-34562-5 |issn=2041-1723 |pmc=9649729 |pmid=36357397|bibcode=2022NatCo..13.6814C }}</ref><ref>{{Cite journal |last1=Fedorov |first1=Oleg |last2=Castex |first2=Josefina |last3=Tallant |first3=Cynthia |last4=Owen |first4=Dafydd R. |last5=Martin |first5=Sarah |last6=Aldeghi |first6=Matteo |last7=Monteiro |first7=Octovia |last8=Filippakopoulos |first8=Panagis |last9=Picaud |first9=Sarah |last10=Trzupek |first10=John D. |last11=Gerstenberger |first11=Brian S. |last12=Bountra |first12=Chas |last13=Willmann |first13=Dominica |last14=Wells |first14=Christopher |last15=Philpott |first15=Martin |date=November 2015 |title=Selective targeting of the BRG/PB1 bromodomains impairs embryonic and trophoblast stem cell maintenance |journal=Science Advances |volume=1 |issue=10 |pages=e1500723 |doi=10.1126/sciadv.1500723 |issn=2375-2548 |pmc=4681344 |pmid=26702435|bibcode=2015SciA....1E0723F }}</ref> and in academic settings<ref>{{Cite journal |last1=Farnaby |first1=William |last2=Koegl |first2=Manfred |last3=Roy |first3=Michael J. |last4=Whitworth |first4=Claire |last5=Diers |first5=Emelyne |last6=Trainor |first6=Nicole |last7=Zollman |first7=David |last8=Steurer |first8=Steffen |last9=Karolyi-Oezguer |first9=Jale |last10=Riedmueller |first10=Carina |last11=Gmaschitz |first11=Teresa |last12=Wachter |first12=Johannes |last13=Dank |first13=Christian |last14=Galant |first14=Michael |last15=Sharps |first15=Bernadette |date=July 2019 |title=BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design |journal=Nature Chemical Biology |volume=15 |issue=7 |pages=672–680 |doi=10.1038/s41589-019-0294-6 |issn=1552-4469 |pmc=6600871 |pmid=31178587}}</ref><ref name=":2" /> have sought to develop [[Enzyme inhibitor|inhibitors]] or [[PROTACs|protein degraders]] of the complex. Small molecules that inactivate SWI/SNF complexes by interfering with ATP hydrolysis<ref name=":1" /><ref name=":3" /> or by causing degradation of key protein subunits<ref name=":4" /> have demonstrated efficacy in pre-clinical studies. Common to many of these settings is the requirement of SWI/SNF activity to promote the expression of genes involved in [[DNA replication|replication]] commitment, specifically for the expression of proteins that promote transition between [[G1 phase|G1]] and [[S phase]] of the [[cell cycle]].<ref name=":5">{{Cite journal |last1=Cermakova |first1=Katerina |last2=Tao |first2=Ling |last3=Dejmek |first3=Milan |last4=Sala |first4=Michal |last5=Montierth |first5=Matthew D. |last6=Chan |first6=Yuen San |last7=Patel |first7=Ivanshi |last8=Chambers |first8=Courtney |last9=Loeza Cabrera |first9=Mario |last10=Hoffman |first10=Dane |last11=Parchem |first11=Ronald J. |last12=Wang |first12=Wenyi |last13=Nencka |first13=Radim |last14=Barbieri |first14=Eveline |last15=Hodges |first15=H. Courtney |date=2023-11-23 |title=Reactivation of the G1 enhancer landscape underlies core circuitry addiction to SWI/SNF |journal=Nucleic Acids Research |volume=52 |issue=1 |pages=4–21 |doi=10.1093/nar/gkad1081 |issn=1362-4962 |pmid=37993417|doi-access=free |pmc=10783513 }}</ref> This area is rapidly evolving and the development of drugs targeting these complexes is ongoing.
== Structure of the SWI/SNF complex ==
[[File:Sniff2.jpg|thumb|516x516px|Domain organization of SWI/SNF: a subfamily within the ATP-Dependent chromatin remodeling complexes]]
Electron microscopy studies of SWI/SNF and RSC (SWI/SNF-B) reveal large, lobed 1.1-1.3 MDa structures.<ref>{{cite journal | vauthors = Asturias FJ, Chung WH, Kornberg RD, Lorch Y | title = Structural analysis of the RSC chromatin-remodeling complex | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 21 | pages = 13477–13480 | date = October 2002 | pmid = 12368485 | pmc = 129698 | doi = 10.1073/pnas.162504299 | doi-access = free | bibcode = 2002PNAS...9913477A }}</ref><ref name="Leschziner_2007">{{cite journal | vauthors = Leschziner AE, Saha A, Wittmeyer J, Zhang Y, Bustamante C, Cairns BR, Nogales E | title = Conformational flexibility in the chromatin remodeler RSC observed by electron microscopy and the orthogonal tilt reconstruction method | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 12 | pages = 4913–4918 | date = March 2007 | pmid = 17360331 | pmc = 1820885 | doi = 10.1073/pnas.0700706104 | doi-access = free | bibcode = 2007PNAS..104.4913L }}</ref><ref>{{cite journal |vauthors=Smith CL, Horowitz-Scherer R, Flanagan JF, Woodcock CL, Peterson CL |date=February 2003 |title=Structural analysis of the yeast SWI/SNF chromatin remodeling complex |url=https://www.nature.com/articles/nsb888 |journal=Nature Structural Biology |volume=10 |issue=2 |pages=141–145 |doi=10.1038/nsb888 |pmid=12524530 |s2cid=3140088}}</ref><ref>{{cite journal | vauthors = Chaban Y, Ezeokonkwo C, Chung WH, Zhang F, Kornberg RD, Maier-Davis B, Lorch Y, Asturias FJ | display-authors = 6 | title = Structure of a RSC-nucleosome complex and insights into chromatin remodeling | journal = Nature Structural & Molecular Biology | volume = 15 | issue = 12 | pages = 1272–1277 | date = December 2008 | pmid = 19029894 | pmc = 2659406 | doi = 10.1038/nsmb.1524 }}</ref> These structures resemble [[RecA]] and cover both sides of a [[Conserved sequence|conserved]] section of the [[ATPase]] domain. The domain also contains a separate domain, [https://www.ebi.ac.uk/interpro/entry/InterPro/IPR014012/ HSA], that is capable of binding actin, and resides on the [[N-terminus]].<ref name = "Clapier_2017">{{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 | pmc = 8127953 | doi = 10.1038/nrm.2017.26 }}</ref> The bromo domain present is responsible for recognizing and binding lysines that have been acetylated.<ref name=":0" /> No atomic-resolution structures of the entire SWI/SNF complex have been obtained to date, due to the protein complex being highly dynamic and composed of many subunits. However, domains and several individual subunits from yeast and mammals have been described. In particular, the cryo-EM structure of the ATPase Snf2 in complex with a nucleosome shows that nucleosomal DNA is locally deformed at the site of binding.<ref>{{cite journal |vauthors=Liu X, Li M, Xia X, Li X, Chen Z |date=April 2017 |title=Mechanism of chromatin remodelling revealed by the Snf2-nucleosome structure |url=https://www.nature.com/articles/nature22036 |journal=Nature |volume=544 |issue=7651 |pages=440–445 |bibcode=2017Natur.544..440L |doi=10.1038/nature22036 |pmid=28424519|s2cid=12392297 }}</ref> A model of the mammalian ATPase SMARCA4 shows similar features,<ref name="Hodges_2018" /> based on the high degree of sequence homology with yeast Snf2. The interface between two subunits, BAF155 (SMARCC1) and BAF47 (SMARCB1) was also resolved, providing important insights into the mechanisms of the SWI/SNF complex assembly pathway.<ref>{{cite journal |vauthors=Yan L, Xie S, Du Y, Qian C |date=June 2017 |title=Structural Insights into BAF47 and BAF155 Complex Formation |url=https://www.sciencedirect.com/science/article/abs/pii/S0022283617301845 |journal=Journal of Molecular Biology |volume=429 |issue=11 |pages=1650–1660 |doi=10.1016/j.jmb.2017.04.008 |pmid=28438634}}</ref>
== SWIB/MDM2 protein domain ==
{{main|MDM2}}
The [[protein domain]], SWIB/MDM2, short for SWI/SNF complex B/MDM2 is an important domain. This protein domain has been found in both SWI/SNF complex B and in the negative regulator of the [[p53]] tumor suppressor MDM2. It has been shown that MDM2 is [[homology (biology)|homologous]] to the SWIB complex.<ref name="pmid12016060">{{cite journal |vauthors=Bennett-Lovsey R, Hart SE, Shirai H, Mizuguchi K |date=April 2002 |title=The SWIB and the MDM2 domains are homologous and share a common fold |url=https://academic.oup.com/bioinformatics/article/18/4/626/243113?login=false |journal=Bioinformatics |volume=18 |issue=4 |pages=626–630 |doi=10.1093/bioinformatics/18.4.626 |pmid=12016060|doi-access=free }}</ref>
=== Function ===
The primary function of the SWIB protein domain is to aid [[gene expression]]. In [[yeast]], this protein domain expresses certain genes, in particular [[betaine-aldehyde dehydrogenase|BADH2]], GAL1, GAL4, and SUC2. It works by increasing [[transcription (genetics)|transcription]]. It has [[ATPase]] activity, meaning it breaks down [[Adenosine triphosphate|ATP]], the basic unit of energy currency. This destabilizes the interaction between DNA and histones. The destabilization that occurs disrupts [[chromatin]] and opens up the transcription-binding domains. Transcription factors can then bind to this site, leading to an increase in transcription.<ref name="pmid11147808"/>
=== Protein interaction ===
The various protein subunits that make up the SWI/SNF complex interact with each other in different configurations to form three distinct types of SWI/SNF complex: canonical BAF (cBAF), polybromo-associated BAF (pBAF) and non-canonical BAF (ncBAF). Specifically, cBAF is currently thought to regulate gene [[Enhancer (genetics)|enhancers]], while pBAF and ncBAF function at regions proximal to gene [[Promoter (genetics)|promoters]].<ref name="pmid34753942">{{cite journal | vauthors = Pagliaroli L, Porazzi P, Curtis AT, Scopa C, Mikkers HM, Freund C, Daxinger L, Deliard S, Welsh SA, Offley S, Ott CA, Calabretta B, Brugmann SA, Santen GW, Trizzino M | display-authors = 6 | title = Inability to switch from ARID1A-BAF to ARID1B-BAF impairs exit from pluripotency and commitment towards neural crest formation in ARID1B-related neurodevelopmental disorders | journal = Nature Communications | volume = 12 | issue = 1 | pages = 6469 | date = November 2021 | pmid = 34753942 | pmc = 8578637 | doi = 10.1038/s41467-021-26810-x | bibcode = 2021NatCo..12.6469P }}</ref> In addition to their many interactions within the family of SWI/SNF related proteins, some subunits such as SNF5 and BAF155 are capable of interacting with transcription factors, such as [[Myc|c-MYC]] and the FOS and JUN family proteins of the [[AP-1 transcription factor|AP-1 complex]].<ref name="pmid33931740">{{cite journal | vauthors = Woodley CM, Romer AS, Wang J, Guarnaccia AD, Elion DL, Maxwell JN, Guerrazzi K, McCann TS, Popay TM, Matlock BK, Flaherty DK, Lorey SL, Liu Q, Tansey WP, Weissmiller AM | display-authors = 6 | title = Multiple interactions of the oncoprotein transcription factor MYC with the SWI/SNF chromatin remodeler | journal = Oncogene | volume = 40 | issue = 20 | pages = 3593–3609 | date = May 2021 | pmid = 33931740 | pmc = 8141032 | doi = 10.1038/s41388-021-01804-7 }}</ref><ref name="pmid29272704">{{cite journal | vauthors = Vierbuchen T, Ling E, Cowley CJ, Couch CH, Wang X, Harmin DA, Roberts CW, Greenberg ME | display-authors = 6 | title = AP-1 Transcription Factors and the BAF Complex Mediate Signal-Dependent Enhancer Selection | journal = Molecular Cell | volume = 68 | issue = 6 | pages = 1067–1082.e12 | date = December 2017 | pmid = 29272704 | pmc = 5744881 | doi = 10.1016/j.molcel.2017.11.026 }}</ref>
=== Structure ===
This protein domain is known to contain one short [[alpha helix]].
== Family members ==
Below is a list of yeast SWI/SNF family members with human and ''Drosophila''<ref>{{Cite journal|title=Table 1 The different components in the yeast, Drosophila and mammalian SWI/SNF complex|journal=Oncogene Including Oncogene Reviews|url=https://www.nature.com/articles/onc20094/tables/1|language=en|issn=1476-5594}}</ref> [[ortholog]]s:<ref name="pmid10601972">{{cite journal | vauthors = Collingwood TN, Urnov FD, Wolffe AP | title = Nuclear receptors: coactivators, corepressors and chromatin remodeling in the control of transcription | journal = Journal of Molecular Endocrinology | volume = 23 | issue = 3 | pages = 255–275 | date = December 1999 | pmid = 10601972 | doi = 10.1677/jme.0.0230255 | doi-access = free }}</ref>
{| class="wikitable"
|-
! Yeast
! Human
!Drosophila
!Function
|-
|{{Yeast Gene|SWI1}}
|[[ARID1A]], [[ARID1B]]
|[[Trithorax-group proteins|OSA]]
|Contains LXXLL [[nuclear receptor]] binding motifs
|-
|{{Yeast Gene|SWI2}}/{{Yeast Gene|SNF2}}
|[[SMARCA2]], [[SMARCA4]]
|[[Trithorax-group proteins|BRM]]
|[[Adenosine triphosphate|ATP]] dependent chromatin remodeling
|-
|{{Yeast Gene|SWI3}}
|[[SMARCC1]], [[SMARCC2]]
|[[Trithorax-group proteins|Moira]]/[https://flybase.org/reports/FBgn0002783.html BAP155]
|Similar sequence; function unknown
|-
|{{Yeast Gene|SWP73}}/[https://www.yeastgenome.org/locus/S000005306 SNF12]
|[[SMARCD1]], [[SMARCD2]], [[SMARCD3]]
|[[Trithorax-group proteins|BAP60]]
|Similar sequence; function unknown
|-
|{{Yeast Gene|SWP61}}/[https://www.yeastgenome.org/locus/SWP61 ARP7]
|[[ACTL6A]], [[ACTL6B]]
|
|[[Actin]]-like protein
|-
|[https://www.yeastgenome.org/locus/S000000493 SNF5]
|[[SMARCB1]]
|[https://flybase.org/reports/FBgn0011715.html SNR1]
|[[Adenosine triphosphate|ATP]] dependent chromatin remodeling
|}
== History ==
The SWI/SNF complex was first discovered in the yeast, ''[[Saccharomyces cerevisiae]]''. It was named after initially screening for mutations that would affect the pathways for both yeast mating types switching (SWI) and sucrose non-fermenting (SNF).<ref name="pmid11147808">{{cite journal |vauthors=Decristofaro MF, Betz BL, Rorie CJ, Reisman DN, Wang W, Weissman BE |date=January 2001 |title=Characterization of SWI/SNF protein expression in human breast cancer cell lines and other malignancies |url=https://onlinelibrary.wiley.com/doi/10.1002/1097-4652(200101)186:1%3C136::AID-JCP1010%3E3.0.CO;2-4 |journal=Journal of Cellular Physiology |volume=186 |issue=1 |pages=136–145 |doi=10.1002/1097-4652(200101)186:1<136::AID-JCP1010>3.0.CO;2-4 |pmid=11147808 |s2cid=25016283}}</ref><ref name=":0" />
== See also ==
*[[Mdm2]]
*[[Chromatin Structure Remodeling (RSC) Complex]]
*[[Transcription coregulator]]
== References==
{{Reflist|32em}}
== External links ==
*[http://www.nextbio.com/b/home/home.nb?q=SWI%2FSNF%20complex&id=39051&type=biogroup&name=SWI%2FSNF%20complex&synonym=#cid=39051&tab=lit Nextbio]
{{Transcription coregulators}}
{{DEFAULTSORT:SWI SNF}}
[[Category:Enzymes]]
[[Category:Transcription coregulators]]