RESEARCH SUMMARY

Our group aim to answer key questions in DNA break repair using novel approaches based on single molecule techniques. DNA breaks are a potentially catastrophic form of DNA damage that can lead to cell death, premature ageing or cancer. Consequently, Nature has developed robust mechanisms to repair DNA breaks that involve dynamic, large scale DNA manipulations by molecular motors and protein machines.

Understanding how these machines work in model organisms will underpin a deeper knowledge of the basic enzymology of DNA repair, and provide important insights into the molecular basis of carcinogenesis.

Single-molecule manipulation and imaging techniques offer huge potential to investigate DNA break repair reactions in completely new ways, providing information that is inaccessible to conventional ensemble experiments. Using single molecule techniques, it is possible to directly observe protein:DNA intermediates, potentially in real time, and to study individual enzymatic cycles in an unsynchronized population.

The aim of our multidisciplinary group is two-fold:

1. To develop novel biophysical instruments for fast atomic force microscopy imaging and single molecule manipulation techniques like optical and magnetic tweezers.

2. To characterize and monitor the real-time dynamics of DNA-repair processes at the single molecule level using this novel instrumentation.

Selected Publications Fuentes-Perez ME, Gwynn EJ, Dillingham MS, Moreno-Herrero F. Using DNA as a fiducial marker to study SMC complex interactions with the atomic force microscope. Biophys J. 2012 Feb 22;102(4):839-48. Yeeles JT, van Aelst K, Dillingham MS, Moreno-Herrero F. Recombination hotspots and single-stranded DNA binding proteins couple DNA translocation to DNA unwinding by the AddAB helicase-nuclease. Mol Cell. 2011 Jun 24;42(6):806-16. Hormeño S, Moreno-Herrero F, Ibarra B, Carrascosa JL, Valpuesta JM, Arias-Gonzalez JR. Condensation prevails over B-A transition in the structure of DNA at low humidity. Biophys J. 2011 Apr 20;100(8):2006-15. Wiggins PA, van der Heijden T, Moreno-Herrero F, Spakowitz A, Phillips R, Widom J, Dekker C, Nelson PC. High flexibility of DNA on short length scales probed by atomic force microscopy. Nat Nanotechnol. 2006 Nov;1(2):137-41. Moreno-Herrero F, de Jager M, Dekker NH, Kanaar R, Wyman C, Dekker C. Mesoscale conformational changes in the DNA-repair complex Rad50/Mre11/Nbs1 upon binding DNA. Nature. 2005 Sep 15;437(7057):440-3.