SMC6

The SMC6 was discovered first in fission yeast as RAD18 (SMC6). It forms a heterodimeric complex with Spr18 (SMC5) protein.{{cite journal | vauthors = Fousteri MI, Lehmann AR | title = A novel SMC protein complex in Schizosaccharomyces pombe contains the Rad18 DNA repair protein | journal = The EMBO Journal | volume = 19 | issue = 7 | pages = 1691–702 | date = April 2000 | pmid = 10747036 | pmc = 310237 | doi = 10.1093/emboj/19.7.1691 }}{{cite journal | vauthors = Lehmann AR, Walicka M, Griffiths DJ, Murray JM, Watts FZ, McCready S, Carr AM | title = The rad18 gene of Schizosaccharomyces pombe defines a new subgroup of the SMC superfamily involved in DNA repair | journal = Molecular and Cellular Biology | volume = 15 | issue = 12 | pages = 7067–80 | date = December 1995 | pmid = 8524274 | pmc = 230962 | doi = 10.1128/mcb.15.12.7067 }} In yeast, SMC5/6 complex has sub-units which consists of SMC5, SMC6 and six nonstructural maintenance of chromosomes (NSE) proteins. Nse1-Nse3-Nse4 subunits bridge the Smc5 head Smc6 and allow the binding of DNA.{{cite journal | vauthors = Palecek J, Vidot S, Feng M, Doherty AJ, Lehmann AR | title = The Smc5-Smc6 DNA repair complex: bridging of the Smc5-Smc6 heads by the KLEISIN, Nse4, and non-Kleisin subunits | journal = The Journal of Biological Chemistry | volume = 281 | issue = 48 | pages = 36952–36959 | date = December 2006 | pmid = 17005570 | doi = 10.1074/jbc.M608004200 | doi-access = free }}{{cite journal | vauthors = Zabrady K, Adamus M, Vondrova L, Liao C, Skoupilova H, Novakova M, Jurcisinova L, Alt A, Oliver AW, Lehmann AR, Palecek JJ | title = Chromatin association of the SMC5/6 complex is dependent on binding of its NSE3 subunit to DNA | journal = Nucleic Acids Research | volume = 44 | issue = 3 | pages = 1064–1079 | date = February 2016 | pmid = 26446992 | pmc = 4756808 | doi = 10.1093/nar/gkv1021 }}{{cite journal | vauthors = Vondrova L, Kolesar P, Adamus M, Nociar M, Oliver AW, Palecek JJ | title = A role of the Nse4 kleisin and Nse1/Nse3 KITE subunits in the ATPase cycle of SMC5/6 | journal = Scientific Reports | volume = 10 | issue = 1 | date = June 2020 | page = 9694 | pmid = 32546830 | pmc = 7297730 | doi = 10.1038/s41598-020-66647-w | bibcode = 2020NatSR..10.9694V }}

It is potentially involved in the Alternative lengthening of telomeres cancer mechanism.{{cite journal | vauthors=Potts PR, Yu H |title=The SMC5/6 complex maintains telomere length in ALT cancer cells through SUMOylation of telomere-binding proteins. |journal=Nat. Struct. Mol. Biol. |volume=14 |issue= 7 |pages= 581–90 |year= 2007 |pmid= 17589526 |doi= 10.1038/nsmb1259 |s2cid=7915836 }}

File:Smc5 6 complex with Nse proteins.png

Nse1-Nse3-Nse4 subunits bridge the heads of the Smc5 and Smc6 proteins and allow the complex to bind DNA. Nse5 and Nse6 form a sub-complex which localizes to the head of the SMC5/6 complex in the budding yeast Saccharomyces cerevisiae, and to the hinges of the SMC5/6 complex in the fission yeast Schizosaccharomyces pombe. The Nse5/6 sub-complex is required for the replication of S. cerevisiae, but has not been characterized as essential in S. pombe. Orthologous proteins to Nse5-Nse6 exist in other eukaryotes, namely ASAP1-SNI1 in Arabidopsis thaliana and SLF1-SLF2 in humans, which are believed have similar function to their Nse counterparts. The localization of SLF1 and SLF2 on the human SMC5/6 complex is unknown.{{Cite journal |last1=Yan |first1=Shunping |last2=Wang |first2=Wei |last3=Marqués |first3=Jorge |last4=Mohan |first4=Rajinikanth |last5=Saleh |first5=Abdelaty |last6=Durrant |first6=Wendy E. |last7=Song |first7=Junqi |last8=Dong |first8=Xinnian |date=2013-11-21 |title=Salicylic Acid Activates DNA Damage Responses to Potentiate Plant Immunity |journal=Molecular Cell |language=en |volume=52 |issue=4 |pages=602–610 |doi=10.1016/j.molcel.2013.09.019 |pmid=24207055 |pmc=3863363 |issn=1097-2765}}{{Cite journal |last1=Diaz |first1=Mariana |last2=Pecinka |first2=Ales |date=2018-01-12 |title=Scaffolding for Repair: Understanding Molecular Functions of the SMC5/6 Complex |journal=Genes |language=en |volume=9 |issue=1 |pages=36 |doi=10.3390/genes9010036 |pmid=29329249 |pmc=5793187 |issn=2073-4425 |doi-access=free }}

The Smc5/6 complex has localization methods which are not heavily conserved. In humans the complex is localized to viral DNA sequences using SMC5/6 localization factors 1 and 2 (SLF1 and SLF2) which contributes to viral resistance.{{Cite journal |last1=Oravcová |first1=Martina |last2=Nie |first2=Minghua |last3=Zilio |first3=Nicola |last4=Maeda |first4=Shintaro |last5=Jami-Alahmadi |first5=Yasaman |last6=Lazzerini-Denchi |first6=Eros |last7=Wohlschlegel |first7=James A |last8=Ulrich |first8=Helle D |last9=Otomo |first9=Takanori |last10=Boddy |first10=Michael N |date=2022-11-14 |editor-last=Chiolo |editor-first=Irene E |editor2-last=Tyler |editor2-first=Jessica K |title=The Nse5/6-like SIMC1-SLF2 complex localizes SMC5/6 to viral replication centers |journal=eLife |volume=11 |pages=e79676 |doi=10.7554/eLife.79676 |doi-access=free |issn=2050-084X |pmc=9708086 |pmid=36373674}} In the plant A. thaliana, this heterodimer can be localized to double stranded breaks for homologous recombination using the SWI3B complex of the SWI/SNF pathway.{{Cite journal |last1=Jiang |first1=Jieming |last2=Mao |first2=Ning |last3=Hu |first3=Huan |last4=Tang |first4=Jiahang |last5=Han |first5=Danlu |last6=Liu |first6=Song |last7=Wu |first7=Qian |last8=Liu |first8=Yiyang |last9=Peng |first9=Changlian |last10=Lai |first10=Jianbin |last11=Yang |first11=Chengwei |date=2019-07-23 |title=A SWI/SNF subunit regulates chromosomal dissociation of structural maintenance complex 5 during DNA repair in plant cells |journal=Proceedings of the National Academy of Sciences |language=en |volume=116 |issue=30 |pages=15288–15296 |doi=10.1073/pnas.1900308116 |doi-access=free |issn=0027-8424 |pmc=6660752 |pmid=31285327|bibcode=2019PNAS..11615288J }} Once localized to the DNA, the SCM5/6 complex non-specifically binds to ~20 DNA base pairs.{{Cite journal |last1=Yu |first1=You |last2=Li |first2=Shibai |last3=Ser |first3=Zheng |last4=Kuang |first4=Huihui |last5=Than |first5=Thane |last6=Guan |first6=Danying |last7=Zhao |first7=Xiaolan |last8=Patel |first8=Dinshaw J. |date=2022-06-07 |title=Cryo-EM structure of DNA-bound Smc5/6 reveals DNA clamping enabled by multi-subunit conformational changes |journal=Proceedings of the National Academy of Sciences |language=en |volume=119 |issue=23 |pages=e2202799119 |doi=10.1073/pnas.2202799119 |doi-access=free |issn=0027-8424 |pmc=9191643 |pmid=35648833|bibcode=2022PNAS..11902799Y }}

Smc6 and Smc5 proteins form a heterodimeric ring-like structure and together with other non-SMC elements form the SMC-5/6 complex. In the worm Caenorhabditis elegans this complex interacts with the HIM-6(BLM) helicase to promote meiotic recombination intermediate processing and chromosome maturation.{{cite journal |vauthors=Hong Y, Sonneville R, Agostinho A, Meier B, Wang B, Blow JJ, Gartner A |title=The SMC-5/6 Complex and the HIM-6 (BLM) Helicase Synergistically Promote Meiotic Recombination Intermediate Processing and Chromosome Maturation during Caenorhabditis elegans Meiosis |journal=PLOS Genet. |volume=12 |issue=3 |pages=e1005872 |year=2016 |pmid=27010650 |pmc=4807058 |doi=10.1371/journal.pgen.1005872 |doi-access=free }} The SMC-5/6 complex in mouse oocytes is essential for the formation of segregation competent bivalents during meiosis.{{cite journal |vauthors=Hwang G, Sun F, O'Brien M, Eppig JJ, Handel MA, Jordan PW |title=SMC5/6 is required for the formation of segregation-competent bivalent chromosomes during meiosis I in mouse oocytes |journal=Development |volume=144 |issue=9 |pages=1648–1660 |year=2017 |pmid=28302748 |doi=10.1242/dev.145607 |pmc=5450844}} In the yeast Saccharomyces cerevisiae, SMC6 is necessary for resistance to DNA damage as well as for damage-induced interchromosomal and sister chromatid recombination.{{cite journal |vauthors=Onoda F, Takeda M, Seki M, Maeda D, Tajima J, Ui A, Yagi H, Enomoto T |title=SMC6 is required for MMS-induced interchromosomal and sister chromatid recombinations in Saccharomyces cerevisiae |journal=DNA Repair (Amst.) |volume=3 |issue=4 |pages=429–39 |year=2004 |pmid=15010319 |doi=10.1016/j.dnarep.2003.12.007 }} In humans, a chromosome breakage syndrome characterized by severe lung disease in early childhood is associated with a mutation in a component of the SMC-5/6 complex.{{cite journal |vauthors=van der Crabben SN, Hennus MP, McGregor GA, Ritter DI, Nagamani SC, Wells OS, Harakalova M, Chinn IK, Alt A, Vondrova L, Hochstenbach R, van Montfrans JM, Terheggen-Lagro SW, van Lieshout S, van Roosmalen MJ, Renkens I, Duran K, Nijman IJ, Kloosterman WP, Hennekam E, Orange JS, van Hasselt PM, Wheeler DA, Palecek JJ, Lehmann AR, Oliver AW, Pearl LH, Plon SE, Murray JM, van Haaften G |title=Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease |journal=J. Clin. Invest. |volume=126 |issue=8 |pages=2881–92 |year=2016 |pmid=27427983 |pmc=4966312 |doi=10.1172/JCI82890 }} Patient’s cells display chromosome rearrangements, micronuclei, sensitivity to DNA damage and defective homologous recombination.

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