Our research focuses on understanding the mechanisms of gene regulation in humans in health and disease. In particular, we study non-canonical RNA/DNA structures, called R-loops. These are three-stranded structures formed during transcription and composed of an RNA/DNA hybrid and a displaced single-stranded DNA. R-loops are formed in all living organisms where they play important biological roles. Dysregulation of R-loops is associated with several human diseases, including cancer and neurodegeneration. We are investigating the molecular mechanisms underlying R-loop functions in humans.
Quick links
R-loop structure.
R-loop-mediated gene silencing in Friedreich’s ataxia.
Functions of R-loops.
In the laboratory, we want to understand the mechanisms underlying regulation of physiological and pathological R-loops in human cells using genome-wide and gene-specific molecular, biochemical and cell biology approaches.
We are investigating the molecular basis of neurodegenerative diseases, associated with pathological R-loops. We study Friedreich ataxia and Fragile X syndrome, two of fifty human diseases with expansion of small nucleotide sequences. It is currently not known how the (GAA)n expansion in frataxin (FXN) gene and the (CGG)n expansion in FMR1 gene leads to their transcriptional repression, resulting in human diseases. We discovered that R-loops are formed in Friedreich ataxia and Fragile X disorders and promote formation of repressive chromatin on the expanded alleles, leading to FXN and FMR1 transcriptional repression.
The results generated in this project will help us to uncover the molecular mechanisms underlying R-loop functions in healthy human cells and also provide a better understanding of the pathology of R-loop-associated human diseases. In the long term, these findings are essential for the development of new therapeutic approaches for cancer and neurodegenerative disorders.
Scientists interested in our work are welcome to contact Natalia Gromak for more details.
2022
RNase H2, mutated in Aicardi-Goutières syndrome, resolves co-transcriptional R-loops to prevent DNA breaks and inflammation.
Cristini, A., Tellier, M., Constantinescu, F., Accalai, C., Albulescu, L.O., Heiringhoff, R., Bery, N., Sordet, O., Murphy, S. and Gromak, N.
Nature Communications – 13(1): 2961.
2020
N6-methyladenosine regulates the stability of RNA:DNA hybrids in human cells.
Abakir, A., Giles, T.C., Cristini, A., Foster, J.M., Dai, N., Starczak, M., Rubio-Roldan, A., Li, M., Eleftheriou, M., Crutchley, J., Flatt, L., Young, L., Gaffney, D.J., Denning, C., Dalhus, B., Emes, R.D., Gackowski, D., Corrêa Jr, I.R., Garcia-Perez, J.L., Klungland, A., Gromak, N.* and Ruzov, A.*
Nature Genetics – 52(1):48-55.
2018
RNA/DNA Hybrid Interactome Identifies DXH9 as a Molecular Player in Transcriptional Termination and R-Loop-Associated DNA Damage.
Cristini, A., Groh, M., Kristiansen, M.S. and Gromak, N.
Cell Reports – 23(6): 1891-1905.
2016
Increased global transcription activity as a mechanism of replication stress in cancer.
Kotsantis, P., Marques Silva, L., Irmscher, S., Jones, R.M., Folkes, L., Gromak, N.* and Petermann, E.*
Nature Communications – 7: 13087.
2011
Human senataxin resolves RNA/DNA hybrids formed at transcriptional pause sites to promote Xrn2-dependent termination.
Skourti-Stathaki, K., Proudfoot, N.J.* and Gromak, N.*
Molecular Cell – 42(6): 794-805.
2014
R-loops associated with triplet repeat expansions promote gene silencing in Friedreich ataxia and fragile X syndrome.
Groh, M., Lufino, M., Wade-Martins, R. and Gromak, N.
PLoS Genetics – 10(5): e1004318.
How Breast Cancer Hijacks a Natural Enzyme to Boost Mutations
October 2023
Natalia Gromak secures prestigious MRC Senior Research Fellowship
June 2023
This highly competitive, 5 year fellowship will support the Gromak group’s investigation of R-loops in health and disease.
Novel insight into transcriptional functions of RNase H2 furthers our understanding of Aicardi Goutières Syndrome pathology
May 2022
Published in Nature Communications, work by the Gromak lab uncovers key new functions for RNase H2 during transcription, and provides molecular explanations for the pathology behind Aicardi Goutières Syndrome. Aicardi Goutières Syndrome (AGS) is a severe neuroinflammatory disease caused by mutations in RNase H2 in more than 50% of the cases. RNase H2 is an...