Different flavours of cohesin complexes
- Different flavors of cohesin complexes and their roles in Cohesinopathies
Cohesin is a ring-shaped multiprotein complex that is crucial for 3D genome organization and control of gene expression during differentiation and development. It also confers sister chromatid cohesion and facilitates DNA damage repair. The cohesin complex exists in three major “flavors”. Besides its core subunits, SMC3, SMC1A and RAD21, cohesin contains in somatic cells one of two orthologous STAG subunits, SA1 or SA2, and a third subunit SA3 in germ cells. How these variable subunits affect the function of the cohesin complex is still not clear. SA1- and SA2-cohesin were initially proposed to organize cohesion at telomeres and centromeres 1, respectively, while SA3 is important for the meiotic cell division 2.
Here we will give a brief overview about the involvement of the different STAG subunits in congenital diseases 3 4 5. We have identified one so far unique patient with an SA2 deletion and full absence of SA2 in skin fibroblasts, where SA3 seems to take over functions of SA2. We will present the molecular characterization of these cells using different approaches to test cohesin functions. To our knowledge this is the first time that a germ-cell specific protein can replace a protein specific for somatic cells.
- ^ Canudas, S., & Smith, S. (2009). Differential regulation of telomere and centromere cohesion by the Scc3 homologues SA1 and SA2, respectively, in human cells. J Cell Biol, 187(2), 165-173. Retrieved from http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19822671
- ^ Pezzi, N., Prieto, I., Kremer, L., Perez Jurado, L. A., Valero, C., Del Mazo, J., . . . Barbero, J. L. (2000). STAG3, a novel gene encoding a protein involved in meiotic chromosome pairing and location of STAG3-related genes flanking the Williams-Beuren syndrome deletion. FASEB J, 14(3), 581-592. Retrieved from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10698974.
- ^ Lehalle, D., Mosca-Boidron, A. L., Begtrup, A., Boute-Benejean, O., Charles, P., Cho, M. T., . . . Faivre, L. (2017). STAG1 mutations cause a novel cohesinopathy characterised by unspecific syndromic intellectual disability. J Med Genet, 54(7), 479-488. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/28119487. doi:10.1136/jmedgenet-2016-104468
- ^ Mullegama, S. V., Klein, S. D., Mulatinho, M. V., Senaratne, T. N., Singh, K., Center, U. C. G., . . . Martinez-Agosto, J. A. (2017). De novo loss-of-function variants in STAG2 are associated with developmental delay, microcephaly, and congenital anomalies. Am J Med Genet A, 173(5), 1319-1327. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/28296084. doi:10.1002/ajmg.a.38207
- ^ (Kruska et al., Brain, manuscript accepted)
Worldconference 2019, Germany and Netherlands, Bad NeuenAhr, published on 31 Jul 2019
