PhD project

Supervisor: Natalia Gromak & Chris Norbury

R-loops are non-canonical RNA/DNA structures, formed in all living organisms where they play crucial roles in regulating gene expression, DNA and histone modifications, generation of antibody diversity, DNA replication and genome stability. The work from the lab have demonstrated that R-loops are also implicated in human diseases, including neurodegeneration and cancer. However, the molecular mechanisms associated with R-loop functions in health and disease are not fully understood.

The main aim of this project is to understand the regulation of R-loops in human cells and uncover the molecular mechanisms which lead to R-loop-associated diseases. We will employ state-of-the-art techniques including CRISPR, Mass Spectrometry, next-generation sequencing, and molecular biology approaches to understand the principles of R-loop biology in health and disease. The results generated in this project will help to understand the pathology of trinucleotide expansion disorders, including Fragile X syndrome and Friedreich ataxia, associated with pathological R-loops. The findings from this project will pave the way for the development of new therapeutic approaches for these disorders.

Keywords:

• Biochemistry;  Cancer / Oncology; Cell Biology; Genetics; Immunology;  Molecular Biology; Neuroscience / Neurology; Pathology

Publications:

• M.Groh and N.Gromak. Out of balance: R-loops in human disease. PLoS Genetics 10(9) (2014).e1004630.
• M.Groh, M.Lufino, R.Wade-Martins, N.Gromak. R-loops formed over expanded repeats cause transcriptional silencing in Friedreich ataxia and Fragile X syndrome. PLoS Genetics 10 (5) (2014). e1004318.
• Skourti-Stathaki, K., Proudfoot, N.J., and Gromak, N. (2011). Human senataxin resolves RNA/DNA hybrids formed at transcriptional pause sites to promote Xrn2-dependent termination. Mol Cell 42, 794-805.
• Kotsantis P, Silva LM, Irmscher S, Jones RM, Folkes L, Gromak N*, Petermann E*. Increased global transcription activity as a mechanism of replication stress in cancer. Nature Commun. 2016 Oct 11;7:13087.
• Cristini A, Groh M, Kristiansen MS, Gromak N. RNA/DNA Hybrid Interactome Identifies DXH9 as a Molecular Player in Transcriptional Termination and R-Loop-Associated DNA Damage. Cell Rep. 2018 May 8;23(6):1891-1905.
• Cristini  A, et al Gromak N. RNase H2, mutated in Aicardi‐Goutières syndrome, resolves co-transcriptional R-loops to prevent DNA breaks and inflammation. Nature Commun, 2022.
• Abakir A,  et al Gromak N*, Ruzov A*. N⁶-methyladenosine regulates the stability of RNA:DNA hybrids in human cells. Nature Genetics. 2020 Jan;52(1):48-55.
• McCann JL, Cristini A, et al Gromak N*, Harris RS*. APOBEC3B regulates R-loops and promotes transcription-associated mutagenesis in cancer. Nature Genetics. 2023 Oct;55(10):1721-1734.