Transcription-Associated Genome Instability

Group leader: Dr Marco Saponaro

Overview

RNA transcription and DNA replication are the two essential processes that use DNA as a substrate. However, DNA can be engaged only by one of them at any given time, with important consequences for genome stability maintenance and human health. Our research focuses on characterising and understanding the mechanisms through which RNA transcription induces genome instability, and how the cells react to this problem.

Our research group

RNA Pol II is the RNA polymerase that transcribes the genes that codify for the proteins in our body. It allows cells to react to the environmental stimuli or to progress through the cell cycle. However, at the same time RNA Pol II transcription is associated with increased genome instability, both increased mutational rates and chromosomal rearrangements.

So far many transcription-associated factors have proved fundamental for genome stability maintenance. However, for most of these factors, we do not know how exactly they affect RNA Pol II transcription, and consequently, how they are inducing genome instability.

We use a combination of genome wide approaches, couple with functional studies and microscopy, to understand how these transcription-associated factors support RNA Pol II transcription, and how genome instability arises in their absence. As well as we are interested in understanding what happens when the transcription and DNA replication machineries collide together. As RNA Pol II transcription and DNA replication use the DNA in our cells as a substrate, and as this DNA can only be engaged by one of them at any given time, these two processes therefore need to be precisely coordinated to avoid reciprocal interference, and we want to determine how this is achieved.

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Current projects

Our group is interested in understanding and characterising how RNA Pol II transcription and DNA replication are coordinated at the genome-wide level, how they coexist without interference, and define the molecular details of their crosstalk. We are also interested in understanding the impact of transcription-induced genome instability in human health, with a particular, but not exclusive, focus on carcinogenesis. In order to characterise this problem, we have identified a set of questions that we are addressing:

  • Can transcription and replication crosstalk together?
  • What happens when transcription and replication collide?
  • How are transcription and replication organised in the genome to avoid conflicting situations?

Research in our group has been generously supported by the University of Birmingham, Wellcome Trust, Royal Society, BBRSC and CRUK.  

Selected publications

Bowry A., Piberger A.L., Rojas P., Saponaro M. and Petermann E. BET Inhibition Induces HEXIM1- and RAD51-Dependent Conflicts between Transcription and Replication. Cell Reports 2018 Nov 20;25(8):2061-2069.e4. 

Williamson L., Saponaro M., Kantidakis T., Boeing S., East P., Mitter R.,KellyG.P., Lobley A., Walker J., Spencer-DeneB., Howell M., Matthews N., Stewart A., and Svejstrup J.Q. DNA damage slows transcript elongation and induces expression of ncRNA isoforms via alternative last exon splicing. Cell 2017 Feb 23; 168(5): 843-855.e13.

Named as one of the ten research articles “Cell Best of 2017”

Related comments:

  • Szempruch A and Guttman M. Linking Protein and RNA Function within the Same Gene. Cell 2017 Feb 34; 168 (5): 753-755  
  • Mushegian AA. UV radiation induces a gene's dual functionality. Science Signaling 2017 Mar 7; 10(469)
  • Conconi A and Bell B. Molecular biology: The long and short of a DNA-damage response. Nature 2017 May 11; 545(7653): 165-166. 

Saponaro M, Kantidakis T, Mitter R, Kelly GP, Heron M, Williams H, Soeding J, Stewart A, and Svejstrup JQ RECQL5 Controls Transcript Elongation and Suppresses Transcription-Associated Genome Instability. Cell 2014 May 22; 157 (5): 1037-49

Related comments:

  • Zlotorynski E Genomic instability: Transcript elongation: pause at your peril. Nat Rev Cancer 2014 May 30;
  • Zlotorynski E Transcription: Transcript elongation: pause at your peril. Nat Rev Mol Cell Biol 2014 Jul. 

Godin-Heymann N, Brabetz S, Murillo MM, Saponaro M, Santos CR, Lobley A, East P, Chakravarty P, Matthews N, Kelly G, Jordan S, Castellano E, Downward J (2015) Tumour-suppression function of KLF12 through regulation of anoikis. Oncogene Oct 12. doi: 10.1038. 

Alzu A, Bermejo R, Begnis M, Lucca C, Piccini D, Carotenuto W, Saponaro M, Brambati A, Cocito A, Foiani M, Liberi G Senataxin associated with replication forks to proect fork integrity across RNA polymerase II-transcribed genes. Cell 2012 Nov 9; 151 (4): 835-46 

Saponaro M, Callahan D, Zheng X, Krejci L, Haber J, Klein H, Liberi G Cdk1 Targets Srs2 to Complete Synthesis-Dependent Strand Annealing and to Promote Recombinational Repair. PLOS Genetics 2010 Feb 26; 6 (2): e1000858

Staff

Enquiries from motivated and enthusiastic researchers interested in joining the lab are welcome at any time. Please email directly to Marco Saponaro .