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 WRAP53 in DNA repair and cancer
As its name indicates, the WD40-encoding RNA antisense to p53 (WRAP53) gene, identified in our laboratory, encodes at least two different functional products: a protein containing WD40 repeats (referred to as WRAP53β) and, via alternative transcriptional start site usage, an antisense transcript that stabilizes p53 (referred to as WRAP53α) (Mahmoudi et al., Molecular Cell 2009).
WRAP53β: guardian of Cajal bodies and genome integrity
Several studies have emphasized the role of the WRAP53β protein (alias WRAP53, WDR79 and TCAB1) as a central player in maintenance of and localization of factors to the nuclear organelles Cajal body. Indeed, without WRAP53β these organelles collapse and cannot re-form (Mahmoudi et al, PLoS Biology, 2010). Cajal bodies collect factors involved in pre-mRNA splicing and telomere maintenance and WRAP53β targets several such factors to Cajal bodies. Recently, our laboratory demonstrated for the first time that WRAP53β also regulates repair of DNA double-strand breaks by localizing the key E3 ligase RNF8 to such lesions (Henriksson et al., Genes & Development 2014). We also discovered the novel involvement of RNA processing factors and noncoding RNAs in DNA repair, and are currently pursuing these observations in depth.
Deregulation of WRAP53β contributes to cancer and neurodegeneration
The WRAP53β protein is associated with several genetic disorders: inherited mutations in WRAP53β cause the cancer predisposition disorder dyskeratosis congenita; patients with spinal muscular atrophy, a neurodegenerative disorder that is the leading genetic cause of infant mortality worldwide, exhibit loss of WRAP53β function; and SNPs in WRAP53 or altered expression of the protein is correlated with an increased risk for various sporadic tumors, including breast, ovarian, head and neck and rectal cancer. The underlying molecular mechanism(s), however, remains unclear. 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.
WRAP53α: a natural p53 antisense transcript
Natural antisense transcripts are a group of regulatory RNAs whose existence has been known for a long time but whose functional significance is still relatively unknown. Studies indicate that up to 70% of all mammalian genes may be regulated by antisense transcripts suggesting a pivotal role of this regulation in eukaryotic gene expression.
The p53 tumor suppressor protects us from cancer and is mutated in around 50% of human tumors. Regulation of p53 has been studied extensively at the protein level. However, recent studies have revealed a critical regulation of p53 at the RNA level. Our discovery of WRAP53α demonstrates for the first time that an antisense transcript has an essential role in the regulation of p53 mRNA (Mahmoudi et al, Molecular Cell 2009). Further studies by us are aimed at understanding the detailed mechanism of WRAP53α-p53 regulation and the role of WRAP53α antisense RNA in carcinogenesis.
Characterize the role of RNA processing in DNA repair and whether disturbance of these functions contributes to neurodegeneration and cancer
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 is the goal of our research, may open new therapeutic possibilities.
More specifically, we are examining the role of the spliceosome in the repair of DNA double-strand breaks and previous studies of a similar nature have led to the discovery of co-transcriptional splicing and transcription-coupled DNA repair.
We are also exploring the involvement of noncoding RNA in DNA repair and elucidate underlying mechanism(s). This could open new avenues for RNA-based approaches for the treatment of cancer.
In addition, we are extending our findings to the cells of patients and murine models, providing more comprehensive understanding of RNA- and splicing-coupled DNA repair in vivo and the potential role of these functions in protection against neurodegeneration and tumor growth.
- The Swedish Research Council (Vetenskapsrådet)
- The Swedish Cancer Society (Cancerfonden)
- Center for innovative medicine (CIMED)
- The Strategic Research Program in Cancer (StratCan)
- The Cancer Society of Stockholm (Cancerföreningen)
- Swedish Society for Medical Research (SSMF)
- Karolinska Institutet
Marianne Farnebo (maiden name: Hammarsund), PhD, Associate Professor, Group leader
Soniya Dhanjal, Lab manager
Stefanie Böhm, Postdoc
Rositsa Dueva, Postdoc
Eleanor O’Brien, Postdoc
Panagiotis Maragozidis, Postdoc
Chiara Pederiva, PhD Student (registered 2015)
Sofie Bergstrand, PhD Student (registered 2017)
Wrap53, a natural p53 antisense transcript required for p53 induction upon DNA damage.
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.
PLoS Biol. 2010 Nov;8(11):e1000521
The scaffold protein WRAP53β orchestrates the ubiquitin response critical for DNA double-strand break repair.
Genes Dev. 2014 Dec;28(24):2726-38
Splicing controls the ubiquitin response during DNA double-strand break repair.
Cell Death Differ. 2016 10;23(10):1648-57