Marianne Farnebo's Group
Our mission - understanding and combating cancer
The integrity of DNA is constantly threatened by numerous intrinsic and environmental sources of damage, which must be repaired accurately to maintain normal cellular functions and prevent diseases, such as cancer and neurodegeneration. Our laboratory is investigating how cells repair their DNA and what factors that contribute to this essential process. Our overall goal is to unravel the complex details of cellular responses to DNA damage and whether these functions are altered in cancer and then build on this knowledge to develop novel strategies for prevention and treatment of cancer.
How do we reach our goal?
To build a strong and creative research team, our laboratory brings together talented people from universities around the world. We combine recent techniques with our local deep knowledge in cell biology and in close collaboration with oncologists and pathologists we create the best possible team for every research task. Together we play part in developing our next breakthrough ideas.
Characterize the role of the RNA processing in DNA repair and whether noncoding RNA is modified and has functions in response to DNA damage
Large-scale screens and whole-genome sequencing have provided a wealth of information concerning the factors and cellular processes that contributes to the maintenance of genomic integrity and thereby help prevent human diseases. Such investigations have led to the surprising identification of RNA processing factors as regulators of DNA repair and revealed that these factors are often mutated in disorders associated with genomic instability, such as cancer. Confirming these findings and uncovering the underlying mechanism(s), which the goal of our research, may open new therapeutic possibilities. More specifically, we are examining the role of the RNA-modifying enzymes fibrillarin and dyskerin and associated RNA in the repair of DNA double-strand breaks. This could open new avenues for RNA-based approaches for the treatment of cancer.
Characterize the role of the RNA-binding protein WRAP53 in DNA repair and cancer
The WD40-encoding RNA antisense to p53 (WRAP53) gene, identified in our laboratory, encodes at least two different functional products: the WRAP53β protein containing WD40 repeats and the WRAP53α RNA antisense to p53 (Mahmoudi et al., Molecular Cell 2009). The WRAP53β protein (alias WRAP53, WDR79 and TCAB1) is a central player in maintenance of and localization of factors to the nuclear organelles Cajal body (Mahmoudi et al, PLoS Biology, 2010). This protein also regulates repair of DNA double-strand breaks by localizing the key E3 ligase RNF8 to such lesions (Henriksson et al., Genes & Development 2014). Loss or deregulation of WRAP53β is associated with disorders: the cancer predisposition disorder dyskeratosis congenita; the neurodegenerative disorder spinal muscular atrophy, and sporadic cancer. Our goal is to provide important insights into the mechanism via which WRAP53β influences cancer development and progression and whether this protein can be targeted in anticancer therapy.
We are also extending our findings to the cells of patients and murine models, providing more comprehensive understanding of WRAP53β- and RNA-coupled DNA repair in vivo and the potential role of these functions in protection against neurodegeneration and tumor growth.
The research in our laboratory is/was funded/supported by:
- Center for innovative medicin (CIMED)
- The Swedish Cancer Society (Cancerfonden)
- The Swedish Childhood Cancer Foundation (Barncancerfonden)
- The Swedish Research Council (Vetenskapsrådet)
- The Strategic Research Program in Cancer (StratCan)
- The Cancer Society of Stockholm (Cancerföreningen)
- Swedish Society for Medical Research (SSMF)
- Worldwide Cancer Research (old AICR)
- Karolinska Institute's Breast Cancer Theme Center (BRECT)
- Karolinska Institutet
- Wenner-Gren Foundation
- Åke Olsson Foundation
Marianne Farnebo Associate Professor, Group leader
Stefanie Böhm, Postdoc
Eleanor O’Brien Postdoc
Julienne O’Rourke Postdoc
Kashyap Dave Senior scientist
Chiara Pederiva, PhD Student
Sofie Bergstrand PhD Student
Davide Trevisan PhD Student
Wrap53, a natural p53 antisense transcript required for p53 induction upon DNA damage.
Mahmoudi S, Henriksson S, Corcoran M, Méndez-Vidal C, Wiman K, Farnebo M
Mol. Cell 2009 Feb;33(4):462-71
WRAP53 is essential for Cajal body formation and for targeting the survival of motor neuron complex to Cajal bodies.
Mahmoudi S, Henriksson S, Weibrecht I, Smith S, Söderberg O, Strömblad S, et al
PLoS Biol. 2010 Nov;8(11):e1000521
The scaffold protein WRAP53β orchestrates the ubiquitin response critical for DNA double-strand break repair.
Henriksson S, Rassoolzadeh H, Hedström E, Coucoravas C, Julner A, Goldstein M, et al
Genes Dev. 2014 Dec;28(24):2726-38
Downregulation of the cancer susceptibility protein WRAP53β in epithelial ovarian cancer leads to defective DNA repair and poor clinical outcome.
Hedström E, Pederiva C, Farnebo J, Nodin B, Jirström K, Brennan D, et al
Cell Death Dis 2015 Oct;6():e1892
Splicing controls the ubiquitin response during DNA double-strand break repair.
Pederiva C, Böhm S, Julner A, Farnebo M
Cell Death Differ. 2016 10;23(10):1648-57