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.
A prerequisite for maintained genome integrity during cell divisions depends on correct gene expression, DNA replication, DNA repair as well as chromosome structure and segregation. The members of the family of conserved Structural Maintenance of Chromosome (SMC-) complexes have overlapping and unique functions during all these processes. Thus, the SMC complex Cohesin, in focus of this project, is necessary for cohesion between sister chromatids until anaphase, thereby promoting high-fidelity chromosome segregation. In addition, it is essential for repair of various types of DNA damage, as well as for shaping the genome in 3D. Deficiency at any level of the Cohesin pathway frequently leads to aneuploidy and genome instability, tumorigenesis and cancer. Indeed, the last ten years it has become clear that Cohesin proteins are among the most frequently mutated in Cancer.
In addition, a group of developmental syndromes called Cohesinopathies are caused by mutations in several of the Cohesin subunits or its regulators. Clinical isolates from these patients are also found to be highly DNA damage sensitive. This together motivates our studies trying to understand the mechanism for tumour development, and Cohesinopathies, driven by deficient DNA damage response and malfunctions of the Cohesin network. Using yeast and human cells as model systems, combined with advanced biochemistry, functional studies and genomic approaches we expect that our studies will open up a new era for understanding the molecular mechanisms for Cohesin during both healthy and malignant cell cycles as well as DNA repair events, and provide novel treatment strategies for Cancer as well as support to CdLS patients. To progress towards these goals, we work on:
- Understanding the molecular mechanisms for the role of the Cohesin network during DSB response and repair, in connection to local and global chromatin structure, as well as transcription
- Determining why and how DSB induction activates de novo cohesion establishment, and if this Damage-Induced cohesion is essential for telomere maintenance
- Evaluating if manipulation of the Cohesin network is a possible new target for Cancer treatment
Recruitment of Scc2/4 to double-strand breaks depends on γH2A and DNA end resection.
Scherzer M, Giordano F, Ferran MS, Ström L
Life Sci Alliance 2022 05;5(5):
Deficiency of Polη in Saccharomyces cerevisiae reveals the impact of transcription on damage-induced cohesion.
Wu PS, Grosser J, Cameron DP, Baranello L, Ström L
PLoS Genet 2021 09;17(9):e1009763
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
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
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