Dynamics of DNA repair

In an average human cell, approximately 100000 DNA damage events occur each day. Our cells contain fascinating machines, called DNA damage repair proteins, which act to repair the diverse different types of chemical modifications which arise when DNA is damaged. We are interested in understanding the molecular mechanisms of how these proteins assemble at sites of DNA damage – particularly strand breaks in the DNA double-helix which are recognized by proteins such as the PARP and Ku families. To study these proteins at high-resoltuion, we develop single-molecule techniques including magnetic tweezers and fluorescence imaging.

Relevant publications:

Bell, N. A. W. & Molloy, J. E. Single-molecule force spectroscopy reveals binding and bridging dynamics of PARP1 and PARP2 at DNA double-strand breaks. Proc. Natl. Acad. Sci. U.S.A. 120, e2214209120 (2023).

Bell, N. A. W. et al. Single-molecule measurements reveal that PARP1 condenses DNA by loop stabilization. Sci. Adv. 7, eabf3641 (2021).

Biophysics of DNA

DNA forms a canonical double-helical structure called B-DNA. It can also form so-called alternative DNA structures such as cruciforms and Z-DNA depending on parameters such as force and supercoiling. We are using force spectroscopy techniques, such as magnetic tweezers and nanopores, together with biochemical methods to study these structural transitions as well as the polymer physics properties of DNA under micromechanical forces.

Relevant publications:

Chen, K. et al. Dynamics of driven polymer transport through a nanopore. Nat. Phys. 17, 1043–1049 (2021).

Bell, N. A. W., Chen, K., Ghosal, S., Ricci, M. & Keyser, U. F. Asymmetric dynamics of DNA entering and exiting a strongly confining nanopore. Nat Commun 8, 380 (2017).

Bell, N. A. W., Muthukumar, M. & Keyser, U. F. Translocation frequency of double-stranded DNA through a solid-state nanopore. Phys. Rev. E 93, 022401 (2016).