University of Dundee

Dr. Constance Alabert

DNA replication in the context of chromatin – Implications for human diseases
Position: 
Principal Investigator
Address: 
School of Life Sciences, University of Dundee, Dundee
Full Telephone: 
+44 (0) 1382 385118, int ext 85118
Email: 

Research

During lineage propagation, cells must duplicate their genetic and epigenetic information to maintain cell identity. However, the mechanisms underlying the maintenance of epigenetic information in dividing cells remain largely unknown. In S phase, progression of DNA replication forks provokes a genome-wide disruption of the epigenetic information. While nucleosomes are rapidly reassembled on newly replicated DNA, full restoration of epigenetic information is not completed until after mitosis. Our aim is to dissect the mechanisms that restore epigenetic information on newly replicated DNA. To this end we take advantage of the Nascent Chromatin Capture (NCC), a novel technology that allows the analysis of proteins associated with newly replicated DNA. We aim to identify and functionally characterize key players in the restoration of the epigenetic information in cycling cells and at specific loci. We aim to further investigate the pathological role of the newly identified chromatin factors, which are deregulated in human diseases as cancer. Altogether, these integrated approaches should provide new insights into the molecular mechanisms that coordinate genome and epigenome maintenance across cell generations.

One of the ways cells control whether genes are turned ‘on’ or ‘off’ is by placing epigenetic ‘tags’ on their DNA. But when cells are dividing, these ‘tags’ are removed, meaning they need to be put back once cells have finished dividing. Our aim is to identify and understand the mechanisms cells use to put these ‘tags’ back in the right place after cells have divided, and to find out whether they play a role in tumor development and growth.

Publications

10 selected publications

Saredi, G., Huang, H., Hammond, C. M., Alabert, C., Bekker-Jensen, S., Forne, I., Reveron-Gomez, N., Foster, B. M., Mlejnkova, L., Bartke, T., Cejka, P., Mailand, N., Imhof, A., Patel, D. J. and Groth, A. (2016) H4K20me0 marks post-replicative chromatin and recruits the TONSL-MMS22L DNA repair complex. Nature. 534, 714-718 view paper

Alabert, C., Barth, T. K., Reveron-Gomez, N., Sidoli, S., Schmidt, A., Jensen, O. N., Imhof, A. and Groth, A. (2015) Two distinct modes for propagation of histone PTMs across the cell cycle. Genes & development. 29, 585-590 view paper

Mejlvang, J., Feng, Y., Alabert, C., Neelsen, K. J., Jasencakova, Z., Zhao, X., Lees, M., Sandelin, A., Pasero, P., Lopes, M. and Groth, A. (2014) New histone supply regulates replication fork speed and PCNA unloading. J Cell Biol. 204, 29-43 view paper

Alabert, C., Bukowski-Wills, J. C., Lee, S. B., Kustatscher, G., Nakamura, K., de Lima Alves, F., Menard, P., Mejlvang, J., Rappsilber, J. and Groth, A. (2014) Nascent chromatin capture proteomics determines chromatin dynamics during DNA replication and identifies unknown fork components. Nature cell biology. 16, 281-293 view paper

Alabert, C. and Groth, A. (2012) Chromatin replication and epigenome maintenance. Nature reviews. Molecular cell biology. 13, 153-167 view paper

Tittel-Elmer, M., Alabert, C., Pasero, P. and Cobb, J. A. (2009) The MRX complex stabilizes the replisome independently of the S phase checkpoint during replication stress. The EMBO journal. 28, 1142-1156 view paper

Falbo, K. B., Alabert, C., Katou, Y., Wu, S., Han, J., Wehr, T., Xiao, J., He, X., Zhang, Z., Shi, Y., Shirahige, K., Pasero, P. and Shen, X. (2009) Involvement of a chromatin remodeling complex in damage tolerance during DNA replication. Nature structural & molecular biology. 16, 1167-1172 view paper

Alabert, C., Bianco, J. N. and Pasero, P. (2009) Differential regulation of homologous recombination at DNA breaks and replication forks by the Mrc1 branch of the S-phase checkpoint. The EMBO journal. 28, 1131-1141 view paper

Flott, S., Alabert, C., Toh, G. W., Toth, R., Sugawara, N., Campbell, D. G., Haber, J. E., Pasero, P. and Rouse, J. (2007) Phosphorylation of Slx4 by Mec1 and Tel1 regulates the single-strand annealing mode of DNA repair in budding yeast. Mol Cell Biol. 27, 6433-6445 view paper

Tourriere, H., Versini, G., Cordon-Preciado, V., Alabert, C. and Pasero, P. (2005) Mrc1 and Tof1 promote replication fork progression and recovery independently of Rad53. Molecular cell. 19, 699-706 view paper