Lab members of the Genome Stability Group and contact information
Project: The effect of interplay between DNA mismatch repair proteins and chromatin on local mutation frequency
Lynch syndrome, a hereditary cancer syndrome, accounts for 2-4% of all colorectal cancer cases and is caused by germline mutations in genes encoding MLH1, MSH2, MSH6, MSH3 and PMS2 proteins, required for DNA mismatch repair (MMR). The DNA mismatch repair machinery is responsible for correcting base-base mismatches and small insertion-deletion loops generated during normal DNA replication and it has been shown to interact with modified histones. I’m interested in finding out how interactions between MMR and chromatin affect the local mutational landscape.
Project: Transcription factor USF1 in spermatogenesis
I am using mouse genetics to elucidate the role(s) of Upstream stimulatory factor 1 (USF1), a ubiquitously expressed transcription factor, in mammalian spermatogenesis. Human USF1 gene mutations and USF1 deficiency in mice both improve cardio-metabolic health, suggesting that targeting USF1 has great therapeutic potential against diabetes and cardiovascular diseases. However, modifying USF1 levels may not be risk-free, as I discovered that Usf1-/- mice display histologically abnormal testes, indicating that USF1 is essential for normal spermatogenesis.
Project: LINE-1 retrotransposition in human cancers
My research primarily focuses on Long Interspersed Elements (LINE-1s), mobile genetic elements capable of autonomous activity in the human genome. Although repressed in normal cells, these “jumping” elements are aberrantly expressed in many cancers, generating new copies and hence making the cancer genome unstable. I am developing strategies to detect tumor-specific somatic LINE-1 insertions and to study their role in tumor progression.
My research focuses on genetic instability in gynecological tumors. I study both benign (uterine leiomyomas and polyps) and malignant tumors (high grade serous ovarian cancer and adult ovarian granulosa cell tumors). We have developed a sensitive PCR-based method, which is able to detect chromosomal rearrangements from solid tissues, cell lines and blood cells. Next generation sequencing data, other PCR-based techniques combined with high quality clinical outpatient data is used as well. The aim is to better understand the biology of tumor cells for both diagnostic and therapeutic purposes.
Project: Contribution of mismatch repair proteins in mammalian genome plasticity.
Mismatch repair (MMR) proteins are responsible for the surveillance and maintenance of DNA integrity. Specifically, MMR proteins are involved in the repair of replication-induced errors such as base-base mismatches, small insertion-deletions, and are also required for the processing of DNA double-stranded breaks formed during meiosis. My research focuses on investigating how reduced MMR protein levels contribute to the instability of tandem repeats (micro- and minisatellites) in vivo. Tandem repeat instability in turn can lead to tumorigenesis, most notably colorectal cancer in humans.
Project: Ex-vivo functional profiling of DNA repair proficiency in primary ovarian cancers to predict response to treatment
Ovarian cancer is a heterogeneous group of malignancies and, because the majority of cancers are diagnosed at advanced stages, the fifth cause of death in women. The standard first-line treatment, which has remained largely unchanged for the past 30 years, consists of surgical cytoreduction and platinum-based chemotherapy. However, approximately half of high-grade serous ovarian cancers (HGSOCs) harbour defects in genes required for DNA damage repair, which makes them especially sensitive to certain DNA damaging chemotherapeutic agents. The purpose of my project is to develop a diagnostic tool based on tumor DNA repair proficiency that can be used to predict patient chemotherapy responses. Results from this study will help to develop patient-specific therapies.
I am interested in genome instability caused by defects in the DNA repair system in humans and how does this affects the phenotype.
Linlin Zhang, MD, PhD
Susanna Jonka, MSc
Denis Dermadi Bebek, PhD
Vanessa Keser, ERASMUS student
Venkatram Yellapragada, MSc
Juha Matilainen, PhD
Henrik Talsi, summer student
Maarit Hakkarainen, lab technician