Lena Ström's Group
Our studies aim at getting a basic understanding of how cells shape and segregate their genetic material that can be applied on genome integrity and development concerns.
Correct DNA repair and chromosome segregation, together with expression of the right genes at the right time and place, are fundamental for the stability of the genome. In addition DNA DSB are induced and repaired to accomplish genomic variation. The SMC (Structural Maintenance of Chromosome) complexes have overlapping and unique functions during all these processes and perform their actions bound to chromatin.
A common loading machinery, the Scc2/4 protein complex, regulates their DNA binding, and is therefore an essential chromosome biology hub. This was firmly established when human SCC2 mutations were found to cause Cornelia de Lange syndrome (CdLS), characterized by severe growth and developmental deficits. Our research is focused on Scc2/4 and Cohesin, one of the SMC complexes, so far implicated in chromosome segregation, DNA repair and gene regulation. We investigate how Scc2/4 functions independently and via Cohesin.
We have found that cells from CdLS patients are DNA damage sensitive because they use a non-efficient alternative method for end joining of DSBs. To broaden this study we are investigating the specific contribution of Scc2 towards the repair of DSBs and how Scc2 mutations found in CdLS isolates may influence this process.
To investigate the regulation of Scc2/4 we are purifying the proteins from budding yeast, and identifying possible chemical modifications of the proteins during the cell cycle and in response to DNA damage by mass spectrometry. By mutational analysis the importance of such modifications will be investigated. Our recent microarray data from yeast showed that expression of numerous genes are affected in the absence of Scc2. Changes in gene expression is now correlated with binding of Cohesin and the Scc2 dependant 3D organization of the genome.
Pei-Shang Wu PhD student
Independent mechanisms recruit the cohesin loader protein NIPBL to sites of DNA damage.
Bot C, Pfeiffer A, Giordano F, Manjeera DE, Dantuma NP, Ström L
J. Cell. Sci. 2017 03;130(6):1134-1146
Post-translational Regulation of DNA Polymerase η, a Connection to Damage-Induced Cohesion in Saccharomyces cerevisiae.
Wu PS, Enervald E, Joelsson A, Palmberg C, Rutishauser D, Hällberg BM, Ström L
Genetics 2020 12;216(4):1009-1022
Localisation of the SMC loading complex Nipbl/Mau2 during mammalian meiotic prophase I.
Visnes T, Giordano F, Kuznetsova A, Suja JA, Lander AD, Calof AL, et al
Chromosoma 2014 Jun;123(3):239-52
A regulatory role for the cohesin loader NIPBL in nonhomologous end joining during immunoglobulin class switch recombination.
Enervald E, Du L, Visnes T, Björkman A, Lindgren E, Wincent J, et al
J. Exp. Med. 2013 Nov;210(12):2503-13
Importance of Polη for damage-induced cohesion reveals differential regulation of cohesion establishment at the break site and genome-wide.
Enervald E, Lindgren E, Katou Y, Shirahige K, Ström L
PLoS Genet. 2013 ;9(1):e1003158