Research Group ROWLAND

Faculty of Medicine, University Medical Centre Utrecht, Dept. of Medical Oncology
Contact: Dr. Benjamin Rowland
E-mail: b.d.rowland@umcutrecht.nl
Website: http://www.umcutrecht.nl/subsite/oncology/Research-groups/Rowland/

General research focus: Building sister chromatid cohesion

During each cell division, the entire genome must be duplicated and separated in such a manner that each of the daughter cells inherits a complete copy of the genome without any alterations. Errors in this process are believed to lie at the basis of cancer and a range of genetic diseases. A key feature for controlling genomic integrity is sister chromatid cohesion, which is mediated by the cohesin complex. The highly conserved cohesin complex forms a huge tri-partite ring structure that is believed to topologically entrap both sister chromatids of each chromosome. Cohesin is essential for the faithful segregation of chromosomes during mitosis. By holding sister chromatids together and resisting the pulling forces of microtubuli up to the moment of bipolar attachment of all chromosomes, cohesin has a fundamental role in ensuring genomic stability and preventing aneuploidy.
While we have learned a lot over the last decade about how cohesin physically holds sister DNAs together and about how these ties are undone at the metaphase to anaphase transition, it is quite striking how little we know about how cohesion is established. The building of cohesion takes place during S phase, but how cohesion establishment and DNA replication are coordinated is largely a mystery. It is not known whether sister DNAs are entrapped by passage of replication forks through cohesin rings that had previously entrapped unreplicated chromatin fibres, or whether entrapment of both sister fibres occurs de novo after the passage of replication forks. Co-entrapment of sister DNAs by the cohesin complex is dependent on a conserved acetyltransferase called Eco1. We showed recently that acetylation of cohesin’s Smc3 core subunit allows the establishment of cohesion by counteracting an inhibitory ‘anti-establishment’ activity associated with cohesin’s Scc3/Rad61/Pds5 regulatory subunits.
Many unanswered questions remain regarding the building of cohesion. For example: What are the mechanistic consequences of Smc3 acetylation? How does the Scc2/Scc4 cohesin loader complex recruit cohesin to chromatin? What is the contribution of ATP hydrolysis by the Smc1/Smc3 heads? And how is cohesion maintained once it is established? These are the kind of questions that keep us awake at night and drive our research. We are attempting to answer such questions using a combination of genetics and biochemistry in budding yeast and mammalian cells. Are you equally fascinated by this topic and would you like to join the Rowland laboratory? Feel free to send an enquiring email to b.d.rowland.at.umcutrecht.nl

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