Biology:SMC1A

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Structural maintenance of chromosomes protein 1A (SMC1A) is a protein that in humans is encoded by the SMC1A gene.[1][2] SMC1A is a subunit of the cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. In somatic cells, cohesin is formed of SMC1A, SMC3, RAD21 and either SA1 or SA2 whereas in meiosis, cohesin is formed of SMC3, SMC1B, REC8 and SA3.

SMC1A is a member of the SMC protein family. Members of this family are key regulators of DNA repair, chromosome condensation and chromosome segregation from bacteria to humans. [3]

Structure

Structure of the interface between SMC3 (blue) and SMC1 (green) (PDB 2WD5) from mice (Kurze et al. 2009)
Structure of the interface between SMC1 (blue) and RAD21 (green) (PDB 1W1W) from budding yeast (Haering et al. 2004)

The domain organisation of SMC proteins is highly conserved and is composed of an N-terminal Walker A motif, coiled-coil, "hinge", coiled-coil and a C-terminal Walker B motif. The protein folds back on itself to form a rod-shaped molecule with a heterodimerisation "hinge" domain at one end and an ABC-type ATPase "head" at the other. These globular domains are separated by a ~50 nm anti-parallel coiled-coil. SMC3 and SMC1 bind via their hinge domains creating V-shaped heterodimers. The N-terminal domain of RAD21 binds to the coiled coil of SMC3 just above the head domain while the C-terminal domain of RAD21 binds the head domain of SMC1. This end to end binding of the SMC3-SMC1-RAD21 trimer creates a closed ring within which DNA can be entrapped.

Function

In addition to entrapping DNA to ensure proper chromosome segregation during the cell cycle, SMC1A, as a component of cohesin, contributes to facilitating inter-chromatid contacts mediating distant-element interactions and to creating chromosome domains called topologically associating domains (TADs). It has been proposed that cohesin promotes the interaction between enhancers and promoters for regulating gene transcription regulation.[4][5][6][7][8][9] The removal of cohesin triggers abnormal TAD topology because loops spanning multiple compartment intervals lead to mixing among loci in different compartments[10][11] As a consequence, loop loss causes gene expression dysregulation.[10] SMC1A also plays a role in spindle pole formation. In fact, in association with SMC3, it is recruited to mitotic spindle poles through interaction with RAE1. The dysregulation of SMC1A (both down- and up-regulation) causes aberrant multi-polar spindles, suggesting that cohesin would function to hold microtubules at the spindle pole.[12][13] Proper cohesion of sister chromatids is a prerequisite for the correct segregation of chromosomes during cell division. The cohesin multiprotein complex is required for sister chromatid cohesion. This complex is composed partly of two structural maintenance of chromosomes (SMC) proteins, SMC3 and either SMC1L2 or the protein encoded by this gene. Most of the cohesin complexes dissociate from the chromosomes before mitosis, although those complexes at the kinetochore remain. Therefore, the encoded protein is thought to be an important part of functional kinetochores. In addition, this protein interacts with BRCA1 and is phosphorylated by ATM, indicating a potential role for this protein in DNA repair. This gene, which belongs to the SMC gene family, is located in an area of the X-chromosome that escapes X inactivation.[2]

Clinical significance

Cornelia de Lange syndrome

Cornelia de Lange syndrome (CdLS) is a rare genetic disorder that presents with variable clinical abnormalities including dysmorphic features, severe growth retardation, global developmental delay, and intellectual disability. The frequency varies from 1:10 000 to 1:30 000 live births without differences between ethnic groups.[14] SMC1A is one of five genes that have been implicated in CdLS. Pathogenic variants in SMC1A, missense and small in frame deletions, are associated with CdLS. SMC1A variants, which maintain the frame of their encoded proteins, are associated with milder CdLS phenotypes with moderate neurocognitive disability and a paucity of major structural defects. The phenotype of SMC1A affected males is more severe than that of mutated females.[15][16][17] Since SMC1A escapes X inactivation, it has been hypothesized that the mechanism in affected females is the dominant-negative effect of the mutated protein.

Genome instability and cancer

SMC1A also takes part in DNA repair. The down-regulation of SMC1A causes genome instability, and CdLS cells carrying SMC1A variants display high level of chromosome aberrations.[18][19][20] Furthermore, SMC1A is phosphorylated on Ser957 and Ser966 residues by ATM and ATR threonine/serine kinases following DNA damage induced by chemical treatment or ionizing radiation. It has been hypothesized that the Breast cancer type 1 susceptibility (BRCA1) gene collaborates in phosphorylating SMC1A, which is required for activation of the S-phase checkpoint allowing blocking of the cell cycle and the repair of DNA.[21][22][19] SMC1A variants have been identified in blood, brain, bladder, and colon cancer.[23][24][25][26][27][28][29] SMC1A plays a pivotal role in colorectal tumorigenesis. Indeed, colorectal tissue acquires extra-copies of SMC1A during cancer development and its expression is significantly stronger in carcinomas than in normal mucosa and early adenoma.[29] Finally, the up-regulation of SMC1A is thought to be a predictor of poor prognosis in colorectal cancer.[30]

Notes

References

  1. ↑ "The human SB1.8 gene (DXS423E) encodes a putative chromosome segregation protein conserved in lower eukaryotes and prokaryotes". Human Molecular Genetics 4 (2): 243–9. February 1995. doi:10.1093/hmg/4.2.243. PMID 7757074. 
  2. ↑ 2.0 2.1 "Entrez Gene: SMC1A structural maintenance of chromosomes 1A". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8243. 
  3. ↑ "Organization of Chromosomal DNA by SMC Complexes". Annual Review of Genetics 53: 445–482. December 2019. doi:10.1146/annurev-genet-112618-043633. PMID 31577909. 
  4. ↑ "Cohesin mediates transcriptional insulation by CCCTC-binding factor". Nature 451 (7180): 796–801. February 2008. doi:10.1038/nature06634. PMID 18235444. Bibcode: 2008Natur.451..796W. 
  5. ↑ "Cohesins form chromosomal cis-interactions at the developmentally regulated IFNG locus". Nature 460 (7253): 410–3. July 2009. doi:10.1038/nature08079. PMID 19458616. Bibcode: 2009Natur.460..410H. 
  6. ↑ "Topological domains in mammalian genomes identified by analysis of chromatin interactions". Nature 485 (7398): 376–80. April 2012. doi:10.1038/nature11082. PMID 22495300. Bibcode: 2012Natur.485..376D. 
  7. ↑ "Spatial partitioning of the regulatory landscape of the X-inactivation centre". Nature 485 (7398): 381–5. April 2012. doi:10.1038/nature11049. PMID 22495304. Bibcode: 2012Natur.485..381N. 
  8. ↑ "Cohesin-based chromatin interactions enable regulated gene expression within preexisting architectural compartments". Genome Research 23 (12): 2066–77. December 2013. doi:10.1101/gr.161620.113. PMID 24002784. 
  9. ↑ "Cohesin-mediated interactions organize chromosomal domain architecture". The EMBO Journal 32 (24): 3119–29. December 2013. doi:10.1038/emboj.2013.237. PMID 24185899. 
  10. ↑ 10.0 10.1 "Cohesin Loss Eliminates All Loop Domains". Cell 171 (2): 305–320.e24. October 2017. doi:10.1016/j.cell.2017.09.026. PMID 28985562. 
  11. ↑ "Two independent modes of chromatin organization revealed by cohesin removal". Nature 551 (7678): 51–56. November 2017. doi:10.1038/nature24281. PMID 29094699. Bibcode: 2017Natur.551...51S. 
  12. ↑ "Interaction between Rae1 and cohesin subunit SMC1 is required for proper spindle formation". Cell Cycle 9 (1): 198–200. January 2010. doi:10.4161/cc.9.1.10431. PMID 20016259. 
  13. ↑ "An update on cohesin function as a 'molecular glue' on chromosomes and spindles". Cell Cycle 9 (9): 1754–8. May 2010. doi:10.4161/cc.9.9.11806. PMID 20436296. 
  14. ↑ "Clinical utility gene card for: Cornelia de Lange syndrome". European Journal of Human Genetics 23 (10): 1431. October 2015. doi:10.1038/ejhg.2014.270. PMID 25537356. 
  15. ↑ "X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations". Nature Genetics 38 (5): 528–30. May 2006. doi:10.1038/ng1779. PMID 16604071. 
  16. ↑ "Incidence and clinical features of X-linked Cornelia de Lange syndrome due to SMC1L1 mutations". Human Mutation 28 (2): 205–6. February 2007. doi:10.1002/humu.9478. PMID 17221863. 
  17. ↑ "Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of cornelia de Lange syndrome with predominant mental retardation". American Journal of Human Genetics 80 (3): 485–94. March 2007. doi:10.1086/511888. PMID 17273969. 
  18. ↑ "Inhibition of BUB1 results in genomic instability and anchorage-independent growth of normal human fibroblasts". Cancer Research 63 (11): 2855–63. June 2003. PMID 12782591. 
  19. ↑ 19.0 19.1 "SMC1 involvement in fragile site expression". Human Molecular Genetics 14 (4): 525–33. February 2005. doi:10.1093/hmg/ddi049. PMID 15640246. 
  20. ↑ "Antioxidant treatment ameliorates phenotypic features of SMC1A-mutated Cornelia de Lange syndrome in vitro and in vivo". Human Molecular Genetics 27 (17): 3002–3011. September 2018. doi:10.1093/hmg/ddy203. PMID 29860495. 
  21. ↑ "Involvement of the cohesin protein, Smc1, in Atm-dependent and independent responses to DNA damage". Genes & Development 16 (5): 560–70. March 2002. doi:10.1101/gad.970602. PMID 11877376. 
  22. ↑ "SMC1 is a downstream effector in the ATM/NBS1 branch of the human S-phase checkpoint". Genes & Development 16 (5): 571–82. March 2002. doi:10.1101/gad.970702. PMID 11877377. 
  23. ↑ "Recurrent inactivation of STAG2 in bladder cancer is not associated with aneuploidy". Nature Genetics 45 (12): 1464–9. December 2013. doi:10.1038/ng.2799. PMID 24121791. 
  24. ↑ "Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia". The New England Journal of Medicine 368 (22): 2059–74. May 2013. doi:10.1056/NEJMoa1301689. PMID 23634996. 
  25. ↑ "Mutant cohesin drives chromosomal instability in early colorectal adenomas". Human Molecular Genetics 23 (25): 6773–8. December 2014. doi:10.1093/hmg/ddu394. PMID 25080505. 
  26. ↑ "The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes". Nature Communications 5: 3630. April 2014. doi:10.1038/ncomms4630. PMID 24710217. Bibcode: 2014NatCo...5.3630H. 
  27. ↑ "Mutations in the cohesin complex in acute myeloid leukemia: clinical and prognostic implications". Blood 123 (6): 914–20. February 2014. doi:10.1182/blood-2013-07-518746. PMID 24335498. 
  28. ↑ "Chronic myelomonocytic leukemia with ETV6-ABL1 rearrangement and SMC1A mutation". Cancer Genetics 238: 31–36. October 2019. doi:10.1016/j.cancergen.2019.07.004. PMID 31425923. 
  29. ↑ 29.0 29.1 "Overexpression of the cohesin-core subunit SMC1A contributes to colorectal cancer development". Journal of Experimental & Clinical Cancer Research 38 (1): 108. March 2019. doi:10.1186/s13046-019-1116-0. PMID 30823889. 
  30. ↑ "Role of SMC1A overexpression as a predictor of poor prognosis in late stage colorectal cancer". BMC Cancer 15: 90. March 2015. doi:10.1186/s12885-015-1085-4. PMID 25884313. 




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