DNA replication and translesion synthesis
The genome of a cell is continuously exposed to different compounds and types of radiation that can alter the chemical composition of the DNA. In response, the cell has developed different types of DNA repair mechanisms that can remove the lesion. When the lesion is not removed before replication is initiated, it can result in a block of the replication machinery that can ultimately lead to cell death. To bypass these blocks, specialized translesion synthesis (TLS) DNA polymerases are recruited to the site of the lesion. The TLS polymerases are capable of DNA synthesis over the damaged DNA, after which the replicative DNA polymerase can continue normal DNA synthesis. These TLS polymerases are generally error prone and have been implicated in drug resistance in bacteria and in different forms of cancer in humans.
We study the interaction between the DNA replication machinery and the translesion synthesis DNA polymerases, using protein X-ray crystallography, electron microscopy and small angle X-ray scattering, as well as multiple biochemical methods.
- Fernandez-Leiro R, Conrad J, Yang JC, Freund SMV, Scheres HWS and Lamers MH. (2017)
Self-correcting mismatches during high-fidelity DNA replication.
Nat Struct Mol Biol, doi:10.1038/nsmb.3348
- Fernandez-Leiro R, Conrad J, Scheres HWS and Lamers MH. (2015)
Cryo-EM structures of the E. coli replicative DNA polymerase reveal dynamic interactions with clamp, exonuclease and τ.
eLife 4: e11134
- Rock, J.M., Lang, U.F., Chase, M.R., Ford, C.B., Gerrick, E.R., Gawande, R., Coscolla, M., Gagneux, S., Fortune, S.M., and Lamers, M.H. (2015)
Replication fidelity in M. tuberculosis is mediated by an ancestral prokaryotic proofreader.
Nature Genetics 47: 677–681
- Barros, T., Guenther, J., Kelch, B., Anaya, J., Prabhakar, A., O'Donnell, M., Kuriyan, J., and Lamers, M.H. (2013)
A structural role for the PHP domain in E. coli DNA polymerase III.
BMC Struct. Biol. 13: 8
- Holding, A.N., Lamers, M.H., Stephens, E., and Skehel, J.M. (2013)
Hekate: software suite for the mass spectrometric analysis and three-dimensional visualization of cross-linked protein samples.
J. Proteome Res. 12: 5923–5933.
- Toste Rêgo, A., Holding, A.N., Kent, H., and Lamers, M.H. (2013)
Architecture of the Pol III-clamp-exonuclease complex reveals key roles of the exonuclease subunit in processive DNA synthesis and repair.
Embo J. 32: 1334–1343.
- Lamers, M.H. and O'Donnell, M. (2008)
A consensus view of DNA binding by the C family replicative DNA polymerases.
Proc Natl Acad Sci 105: 20565-20566.
- Lamers, M.H., Georgescu, R.E., Lee, S.G., O'Donnell, M. and Kuriyan, J. (2006)
Crystal structure of the catalytic alpha subunit of E. coli replicative DNA polymerase III.
Cell 126: 881-892.
- Lamers, M.H., Perrakis, A., Enzlin, J.H., Winterwerp, H.H.K., de Wind, N. and Sixma, T.K. (2000)
The crystal structure of DNA mismatch repair protein MutS binding to a G:T mismatch.
Nature 407: 711-717.
- Marike Worrall (nee van Roon)
- Soledad Banos Mateos
- Emma Gleave
- Gengjing Zhao