Molecular Biophysics of DNA repair nanomachines

FMoreno

 

Fernando Moreno-Herrero

Group Leader

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Research summary

DNA breaks are a potentially catastrophic form of DNA damage that can lead to cell death, premature ageing or cancer. Our group aim to answer key questions in DNA break repair using novel approaches based on single molecule techniques.

 

Publications

Martín-García B, Martín-González A, Carrasco C, Hernández-Arriaga AM, Ruíz-Quero R, Díaz-Orejas R, Aicart-Ramos C, Moreno-Herrero F, Oliva MA. The TubR-centromere complex adopts a double-ring segrosome structure in Type III partition systems Nucleic Acids Res. 2018 May 14. doi: 10.1093/nar/gky370.

Madariaga-Marcos J, Hormeño S, Pastrana CL, Fisher GLM, Dillingham MS, Moreno-Herrero F. Force determination in lateral magnetic tweezers combined with TIRF microscopy. Nanoscale. 2018 Feb 20. doi: 10.1039/c7nr07344e

Fisher GL*, Pastrana CL*, Higman VA*, Koh A, Taylor JA, Butterer A, Craggs T, Sobott F, Murray H, Crump MP, Moreno-Herrero F, Dillingham MS.The structural basis for dynamic DNA binding and bridging interactions which condense the bacterial centromere. Elife. 2017 Dec 15;6. pii: e28086.

Alberto Marin-Gonzalez, Jose Guilherme Vilhena, Rubén Pérez, and Fernando Moreno-Herrero. Understanding the mechanical response of double-stranded DNA and RNA under constant stretching forces using all-atom molecular dynamics. Proc Natl Acad Sci U S A. 2017 Jun 20. pii: 201705642

Pastrana CL, Carrasco C, Akhtar P, Leuba SH, Khan SA, Moreno-Herrero F. Force and twist dependence of RepC nicking activity on torsionally-constrained DNA molecule. Nucleic Acids Res 2016; 44: 8885-8896

 

Fig2Moreno HerreroWe develop and employ single-molecule techniques to study the inner workings of protein machines involved in DNA repair processes and maintenance of chromosome structures. We are also interested in studying the mechanical properties of nucleic acids and their interaction with proteins, using novel single-molecule approaches based on atomic force microscopy (AFM) and magnetic tweezers.

In the last two years, we developed temperature-controlled magnetic tweezers to study the kinetics of double-stranded DNA processing by the protein complex AddAB, a helicase nuclease involved in dsDNA break repair. This method allowed us to determine the kinetic barrier of the enzymatic reaction. During this research, we also deepened our knowledge of the mechanism of Chi regulatory sequence recognition by AddAB, using a combination of biophysical and biochemical techniques. AddAB has a molecular latch that enables part of the DNA substrate to evade degradation beyond Chi. Our data suggest a model in which allosteric communication between Chi binding and the latch ensures quality control during recombination hotspot recognition.

We also investigated the ParB protein interaction with centromere-like DNA sequences, called parS, located near the origin of replication. We determined that ParB binds parS as a homodimer and displays positive co-operativity associated with formation of larger, poorly defined nucleoprotein complexes. Our data demonstrated that non-specific ParB binding leads to DNA condensation that is reversible by protein unbinding or force. These findings have consequences for chromosome condensation and segregation. Other ongoing projects using biophysical methods include study of the initiation of replication by the rolling circle mechanism and use of fluorescence microscopy and force spectroscopy in a combined magnetictweezers TIRF setup developed in-house. In addition, we use molecular dynamics methods to understand the effect of force in the mechanical properties of DNA and RNA. Finally, we have pushed the resolution limits of our AFM to resolve the A-form subhelical pitch periodicity of doublestranded RNA in near-physiological conditions.

 

Fig1Moreno Herrero

 

grupoMoreno HerreroRed

 

Name
Position
Contact
Fernando Moreno-Herrero Principal investigator
Adriana Gil Gil Postdoctoral scientist
Carolina Carrasco Pulido Postdoctoral scientist
Silvia Hormeño Postdoctoral scientist
Guilherme Vilhena Postdoctoral scientist
Clara Aicart Ramos Postdoctoral scientist
César López Pastrana Predoctoral scientists
Julene Madariaga Marcos Predoctoral scientists
Alejandro Martín González Predoctoral scientists
Alberto Marín González Predoctoral scientists
Maria Teresa Arranz Computer Engineering

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