Laura Baranello's group
Topoisomerases, chromatin biology and cancer
Cancer is a biologically complex disease that causes significant deaths in the human population. Pharmaceuticals that inhibit enzymes called topoisomerases are effective at killing many types of cancer cells. Unfortunately, the body’s healthy cells are also damaged by this treatment. Development of tumor-specific topoisomerase inhibitor-based therapies will require better knowledge of the mechanism of topoisomerase activity.
Topoisomerases are important cellular enzymes; they are involved in processes in which genes are copied, or when DNA is replicated prior to cell division. They unwind the DNA double helix, so that the enzymes that are going to transcribe genes or replicate DNA strands are able to do so.
Although conventionally considered to be constitutively active enzymes, recent evidence show that topoisomerases execute their function through regulatory interactions with partner proteins that modulate their activity to affect the transcriptional outcome. Understanding the mechanism of this regulation might provide a new strategy to affect topoisomerase activity in cancer cells.
Our ongoing and future investigations are based on these findings. We use a variety of approaches including biochemical assays, next-generation sequencing techniques, genome editing and drug screens to:
- Identify new proteins regulating topoisomerase 1 and topoisomerase 2 activity. Among the potential partners we focus on transcription and chromatin factors.
- Understand the molecular details of how topoisomerases are regulated by their protein partners during transcription.
- Identify drugs targeting the stimulation of topoisomerase activity in cancer cells.
|Laura Baranello||Research group leader|
|Francesca Carrierro||Graduate student|
|Roberta D'Aulerio||Graduate student|
- Wallenberg Foundation (Wallenberg Academy Fellow)
- Swedish Research Council (Starting Grant)
- Karolinska Institutet
- VINNOVA (VINNMER Marie Curie Incoming)
Our research is performed with a number of national and international collaborators:
Dr. Camilla Sjogren, Karolinska Institutet
Dr. David Levens, National Institutes of Health, USA
Dr. Craig Thomas, National Institutes of Health
Permanganate/S1 Nuclease Footprinting Reveals Non-B DNA Structures with Regulatory Potential across a Mammalian Genome.
Cell Syst 2017 Mar;4(3):344-356.e7
RNA Polymerase II Regulates Topoisomerase 1 Activity to Favor Efficient Transcription.
Cell 2016 Apr;165(2):357-71
DNA break mapping reveals topoisomerase II activity genome-wide.
Int J Mol Sci 2014 Jul;15(7):13111-22
CTCF and cohesin cooperate to organize the 3D structure of the mammalian genome.
Proc. Natl. Acad. Sci. U.S.A. 2014 Jan;111(3):889-90
DNA topology and transcription.
Transcription-dependent dynamic supercoiling is a short-range genomic force.
Nat. Struct. Mol. Biol. 2013 Mar;20(3):396-403
The importance of being supercoiled: how DNA mechanics regulate dynamic processes.
Biochim. Biophys. Acta 2012 Jul;1819(7):632-8
DNA topoisomerase I inhibition by camptothecin induces escape of RNA polymerase II from promoter-proximal pause site, antisense transcription and histone acetylation at the human HIF-1alpha gene locus.
Nucleic Acids Res. 2010 Jan;38(1):159-71