SMC6 explained

Structural maintenance of chromosomes protein 6 is a protein that in humans is encoded by the SMC6 gene.^{[1] [2]}

Structure

The SMC6 was discovered first in fission yeast as RAD18 (SMC6). It forms a heterodimeric complex with Spr18 (SMC5) protein.^{[3] [4]} 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.^{[5] [6] [7]}

It is potentially involved in the Alternative lengthening of telomeres cancer mechanism.^[8]

Nse subunits

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.^{[9] [10]}

Localization

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.^[11] 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.^[12] Once localized to the DNA, the SCM5/6 complex non-specifically binds to ~20 DNA base pairs.^[13]

Role in recombination and meiosis

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.^[14] The SMC-5/6 complex in mouse oocytes is essential for the formation of segregation competent bivalents during meiosis.^[15] In the yeast Saccharomyces cerevisiae, SMC6 is necessary for resistance to DNA damage as well as for damage-induced interchromosomal and sister chromatid recombination.^[16] 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.^[17] Patient’s cells display chromosome rearrangements, micronuclei, sensitivity to DNA damage and defective homologous recombination.

Further reading

• Hartley JL, Temple GF, Brasch MA . DNA cloning using in vitro site-specific recombination. . Genome Res. . 10 . 11 . 1788–95 . 2001 . 11076863 . 10.1101/gr.143000 . 310948 .
• Simpson JC, Wellenreuther R, Poustka A, etal . Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing. . EMBO Rep. . 1 . 3 . 287–92 . 2001 . 11256614 . 10.1093/embo-reports/kvd058 . 1083732 .
• Taylor EM, Moghraby JS, Lees JH, etal . Characterization of a novel human SMC heterodimer homologous to the Schizosaccharomyces pombe Rad18/Spr18 complex. . Mol. Biol. Cell . 12 . 6 . 1583–94 . 2001 . 11408570 . 10.1091/mbc.12.6.1583. 37326 .
• Strausberg RL, Feingold EA, Grouse LH, etal . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . 2002PNAS...9916899M . free .
• Ota T, Suzuki Y, Nishikawa T, etal . Complete sequencing and characterization of 21,243 full-length human cDNAs. . Nat. Genet. . 36 . 1 . 40–5 . 2004 . 14702039 . 10.1038/ng1285 . free .
• Gerhard DS, Wagner L, Feingold EA, etal . The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). . Genome Res. . 14 . 10B . 2121–7 . 2004 . 15489334 . 10.1101/gr.2596504 . 528928 .
• Wiemann S, Arlt D, Huber W, etal . From ORFeome to biology: a functional genomics pipeline. . Genome Res. . 14 . 10B . 2136–44 . 2004 . 15489336 . 10.1101/gr.2576704 . 528930 .
• Hillier LW, Graves TA, Fulton RS, etal . Generation and annotation of the DNA sequences of human chromosomes 2 and 4. . Nature . 434 . 7034 . 724–31 . 2005 . 15815621 . 10.1038/nature03466 . 2005Natur.434..724H . free .
• Potts PR, Yu H . Human MMS21/NSE2 is a SUMO ligase required for DNA repair. . Mol. Cell. Biol. . 25 . 16 . 7021–32 . 2005 . 16055714 . 10.1128/MCB.25.16.7021-7032.2005 . 1190242 .
• Mehrle A, Rosenfelder H, Schupp I, etal . The LIFEdb database in 2006. . Nucleic Acids Res. . 34 . Database issue . D415–8 . 2006 . 16381901 . 10.1093/nar/gkj139 . 1347501 .
• Potts PR, Porteus MH, Yu H . Human SMC5/6 complex promotes sister chromatid homologous recombination by recruiting the SMC1/3 cohesin complex to double-strand breaks. . EMBO J. . 25 . 14 . 3377–88 . 2006 . 16810316 . 10.1038/sj.emboj.7601218 . 1523187 .

Notes and References

1. Wiemann S, Weil B, Wellenreuther R, Gassenhuber J, Glassl S, Ansorge W, Bocher M, Blocker H, Bauersachs S, Blum H, Lauber J, Dusterhoft A, Beyer A, Kohrer K, Strack N, Mewes HW, Ottenwalder B, Obermaier B, Tampe J, Heubner D, Wambutt R, Korn B, Klein M, Poustka A . Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs . Genome Res . 11 . 3 . 422–35 . Mar 2001 . 11230166 . 311072 . 10.1101/gr.GR1547R .
2. Web site: Entrez Gene: SMC6 structural maintenance of chromosomes 6.
3. Fousteri MI, Lehmann AR . A novel SMC protein complex in Schizosaccharomyces pombe contains the Rad18 DNA repair protein . The EMBO Journal . 19 . 7 . 1691–702 . April 2000 . 10747036 . 310237 . 10.1093/emboj/19.7.1691 .
4. Lehmann AR, Walicka M, Griffiths DJ, Murray JM, Watts FZ, McCready S, Carr AM . The rad18 gene of Schizosaccharomyces pombe defines a new subgroup of the SMC superfamily involved in DNA repair . Molecular and Cellular Biology . 15 . 12 . 7067–80 . December 1995 . 8524274 . 230962 . 10.1128/mcb.15.12.7067 .
5. Palecek J, Vidot S, Feng M, Doherty AJ, Lehmann AR . The Smc5-Smc6 DNA repair complex: bridging of the Smc5-Smc6 heads by the KLEISIN, Nse4, and non-Kleisin subunits . The Journal of Biological Chemistry . 281 . 48 . 36952–36959 . December 2006 . 17005570 . 10.1074/jbc.M608004200 . free .
6. Zabrady K, Adamus M, Vondrova L, Liao C, Skoupilova H, Novakova M, Jurcisinova L, Alt A, Oliver AW, Lehmann AR, Palecek JJ . Chromatin association of the SMC5/6 complex is dependent on binding of its NSE3 subunit to DNA . Nucleic Acids Research . 44 . 3 . 1064–1079 . February 2016 . 26446992 . 4756808 . 10.1093/nar/gkv1021 .
7. Vondrova L, Kolesar P, Adamus M, Nociar M, Oliver AW, Palecek JJ . A role of the Nse4 kleisin and Nse1/Nse3 KITE subunits in the ATPase cycle of SMC5/6 . Scientific Reports . 10 . 1 . June 2020 . 9694 . 32546830 . 7297730 . 10.1038/s41598-020-66647-w . 2020NatSR..10.9694V .
8. Potts PR, Yu H . The SMC5/6 complex maintains telomere length in ALT cancer cells through SUMOylation of telomere-binding proteins. . Nat. Struct. Mol. Biol. . 14 . 7 . 581–90 . 2007 . 17589526 . 10.1038/nsmb1259 . 7915836 .
9. Yan . Shunping . Wang . Wei . Marqués . Jorge . Mohan . Rajinikanth . Saleh . Abdelaty . Durrant . Wendy E. . Song . Junqi . Dong . Xinnian . 2013-11-21 . Salicylic Acid Activates DNA Damage Responses to Potentiate Plant Immunity . Molecular Cell . en . 52 . 4 . 602–610 . 10.1016/j.molcel.2013.09.019 . 24207055 . 3863363 . 1097-2765.
10. Diaz . Mariana . Pecinka . Ales . 2018-01-12 . Scaffolding for Repair: Understanding Molecular Functions of the SMC5/6 Complex . Genes . en . 9 . 1 . 36 . 10.3390/genes9010036 . 29329249 . 5793187 . 2073-4425 . free .
11. Oravcová . Martina . Nie . Minghua . Zilio . Nicola . Maeda . Shintaro . Jami-Alahmadi . Yasaman . Lazzerini-Denchi . Eros . Wohlschlegel . James A . Ulrich . Helle D . Otomo . Takanori . Boddy . Michael N . 2022-11-14 . Chiolo . Irene E . Tyler . Jessica K . The Nse5/6-like SIMC1-SLF2 complex localizes SMC5/6 to viral replication centers . eLife . 11 . e79676 . 10.7554/eLife.79676 . free . 2050-084X . 9708086 . 36373674.
12. Jiang . Jieming . Mao . Ning . Hu . Huan . Tang . Jiahang . Han . Danlu . Liu . Song . Wu . Qian . Liu . Yiyang . Peng . Changlian . Lai . Jianbin . Yang . Chengwei . 2019-07-23 . A SWI/SNF subunit regulates chromosomal dissociation of structural maintenance complex 5 during DNA repair in plant cells . Proceedings of the National Academy of Sciences . en . 116 . 30 . 15288–15296 . 10.1073/pnas.1900308116 . free . 0027-8424 . 6660752 . 31285327. 2019PNAS..11615288J .
13. Yu . You . Li . Shibai . Ser . Zheng . Kuang . Huihui . Than . Thane . Guan . Danying . Zhao . Xiaolan . Patel . Dinshaw J. . 2022-06-07 . Cryo-EM structure of DNA-bound Smc5/6 reveals DNA clamping enabled by multi-subunit conformational changes . Proceedings of the National Academy of Sciences . en . 119 . 23 . e2202799119 . 10.1073/pnas.2202799119 . free . 0027-8424 . 9191643 . 35648833. 2022PNAS..11902799Y .
14. Hong Y, Sonneville R, Agostinho A, Meier B, Wang B, Blow JJ, Gartner A . The SMC-5/6 Complex and the HIM-6 (BLM) Helicase Synergistically Promote Meiotic Recombination Intermediate Processing and Chromosome Maturation during Caenorhabditis elegans Meiosis . PLOS Genet. . 12 . 3 . e1005872 . 2016 . 27010650 . 4807058 . 10.1371/journal.pgen.1005872 . free .
15. Hwang G, Sun F, O'Brien M, Eppig JJ, Handel MA, Jordan PW . SMC5/6 is required for the formation of segregation-competent bivalent chromosomes during meiosis I in mouse oocytes . Development . 144 . 9 . 1648–1660 . 2017 . 28302748 . 10.1242/dev.145607 . 5450844.
16. Onoda F, Takeda M, Seki M, Maeda D, Tajima J, Ui A, Yagi H, Enomoto T . SMC6 is required for MMS-induced interchromosomal and sister chromatid recombinations in Saccharomyces cerevisiae . DNA Repair (Amst.) . 3 . 4 . 429–39 . 2004 . 15010319 . 10.1016/j.dnarep.2003.12.007 .
17. 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 . Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease . J. Clin. Invest. . 126 . 8 . 2881–92 . 2016 . 27427983 . 4966312 . 10.1172/JCI82890 .