Genome-embedded ribonucleotides: mechanistic insights and therapeutic implications

Olga Murina’s interest in the control of genome stability began while studying for a BSc then an MSc in biology at St. Petersburg State University.  In 2009, Olga joined the Cancer Biology PhD Program at the Institute of Molecular Cancer Research (IMCR) at the University of Zurich, Switzerland, investigating the relationship between Fanconi anaemia and homologous recombination DNA repair pathways in the lab of Alessandro Sartori.  At the end of 2014, Olga joined the lab of Andrew Jackson at the MRC Human Genetics Unit at the University of Edinburgh, where her postdoctoral work has been supported by Swiss National Science Foundation (SNSF) and EMBO Long-Term Fellowships.  Olga has made two major breakthroughs in her postdoc work.  Firstly, she identified the E3 ubiquitin ligase TRAIP as a novel microcephalic dwarfism gene critical for maintaining genome integrity during DNA replication.  More recently, her work has focused on the detection and removal of ribonucleotides embedded in genomic DNA, in collaboration with Daniel Durocher’s laboratory at the Lunenfeld-Tannenbaum Research Institute, Toronto.  Olga’s second breakthrough came with the demonstration that deficiency in RNase H2, an enzyme critical for the removal of ribonucleotides embedded in the genome, causes synthetic lethality with PARP inhibitors – these are a novel class of drugs well known for their toxicity in tumours with defects in homologous recombination, caused by mutations in BRCA1 or BRCA2 for example.  As well as providing major new insights into the interdependencies of DNA repair pathways, Olga’s findings provide an opportunity to expand the use of PARP inhibitors in cancer therapy given reports of frequent deletion of RNASEH2B in metastatic prostate cancer and chronic lymphocytic leukaemia.  In 2019, Olga’s research achievements were recognized when she received a prestigious Early Career Research Award from SULSA (Scottish Universities Life Sciences Alliance), given to “outstanding early career scientists whose work shows excellent potential to make an impact in the field of life sciences”.

 

Key publications:

CRISPR screens identify genomic ribonucleotides as a source of PARP-trapping lesions.

Zimmermann M*, Murina O*, Reijns MAM, Agathanggelou A, Challis R, Tarnauskaitė Ž, Muir M, Fluteau A, Aregger M, McEwan A, Yuan W, Clarke M, Lambros MB, Paneesha S, Moss P, Chandrashekhar M, Angers S, Moffat J, Brunton VG, Hart T, de Bono J, Stankovic T, Jackson AP, Durocher D.

Nature 2018 Jul; 559(7713):285-289. *- Equal contribution

 

cGAS surveillance of micronuclei links genome instability to innate immunity.

Mackenzie KJ, Carroll P, Martin CA, Murina O, Fluteau A, Simpson DJ, Olova N, Sutcliffe H, Rainger JK, Leitch A, Osborn RT, Wheeler AP, Nowotny M, Gilbert N, Chandra T, Reijns MAM, Jackson AP.

Nature 2017 Aug; 548(7668):461-465.

 

TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism.

Harley ME*, Murina O*, Leitch A, Higgs MR, Bicknell LS, Yigit G, Blackford AN, TRAIP consortium and co-authors, Jackson SP, Hurles ME, Wollnik B, Stewart GS, Jackson AP.

Nature Genetics 2016 Jan; 48(1):36-43. *- Equal contribution

 

FANCD2 and CtIP cooperate to repair DNA interstrand crosslinks.

Murina O, von Aesch C, Karakus U, Ferretti LP, Bolck HA, Hänggi K, Sartori AA.

Cell Reports 2014 May 22;7(4):1030-8. 

 

Prolyl isomerase PIN1 regulates DNA double-strand break repair by counteracting DNA end resection.

Steger M, Murina O, Hühn D, Ferretti LP, Walser R, Hänggi K, Lafranchi L, Neugebauer C, Paliwal S, Janscak P, Gerrits B, Del Sal G, Zerbe O, Sartori AA.

Mol Cell 2013 May 9;50(3):333-43.