John Rouse's Research Group

Pubmed | Biography

Chromosome stability and DNA repair

Our chromosomes are frequently subjected to insults that damage DNA, and if not rectified the resulting DNA lesions can cause mutations and human disease.

My team studies the molecular mechanisms underlying the signalling and repair of DNA damage, especially those that perturb DNA replication, with emphasis on control of these by phosphorylation and ubiquitylation. We are particularly keen to understand how derailment of DNA repair causes disease. We have become interested in how cells repair DNA inter-strand crosslinks (ICLs), lesions that potently block DNA replication. ICL repair is important to study as defective ICL repair gives rise to Fanconi anemia (FA), a recessive disorder characterized by developmental defects, bone marrow failure and cancer predisposition. Furthermore, some anti-cancer drugs rely on induction of ICLs, and therefore understanding how ICLs are repaired may pave the way for sensitizing cancers to these drugs.

We have discovered a host of factors that are instrumental in repairing ICLs and other DNA lesions. For example, ubiquitin-dependent recruitment of FAN1 to sites of DNA damage suppresses chromosome abnormalities and cancer through promoting cleaving of DNA at sites in the genome where DNA replication forks stall to promote fork repair. Another example is the SLX4 “molecular toolkit” which removes tangles from chromosomes, in a ubiquitin-dependent manner, so that they can segregate properly. These DNA repair factors are excellent drug targets, which provide new therapies for diseases such as cancer and improve the effectiveness of existing chemotherapies.

Clockwise from back left: Ivan M. Muñoz, Taran Khanam, John Rouse, Rathan Jadav, Meghan Slean, Michael Morgan, Maithili Shroff, Florian Weiland, Laura Feeney
Clockwise from back left: Ivan M. Muñoz, Taran Khanam, John Rouse, Rathan Jadav, Meghan Slean, Michael Morgan, Maithili Shroff, Florian Weiland, Laura Feeney


Eduardo de la Vega | Postdoctoral Researcher
Mateusz Gregorczyk | PhD Student
Rathan Jadav | Postdoctoral Researcher
Taran Khanam | Postdoctoral Researcher
Ivan M. Muñoz | Postdoctoral Researcher
Giulia Saredi | Postdoctoral Researcher
Junfang Song | Postdoctoral Researcher
Thomas Carroll | Postdoctoral Researcher

Selected Publications

1   Davis, E. J., Lachaud, C., Appleton, P., Macartney, T. J., Nathke, I., Rouse, J. (2012) DVC1 (C1orf124) recruits the p97 protein segregase to sites of DNA damage Nat Struct Mol Biol 19 1093-1100
2   Castor, D., Nair, N., Declais, A. C., Lachaud, C., Toth, R., Macartney, T. J., Lilley, D. M., Arthur, J. S., Rouse, J. (2013) Cooperative control of holliday junction resolution and DNA repair by the SLX1 and MUS81-EME1 nucleases Mol Cell 52 221-233
3   Wilson, J. S., Tejera, A. M., Castor, D., Toth, R., Blasco, M. A., Rouse, J. (2013) Localization-dependent and -independent roles of SLX4 in regulating telomeres Cell Rep 4 853-860
4   Lachaud, C., Moreno, A., Marchesi, F., Toth, R., Blow, J. J., Rouse, J. (2016) Ubiquitinated Fancd2 recruits Fan1 to stalled replication forks to prevent genome instability Science 351 846-849
5   Lachaud, C., Slean, M., Marchesi, F., Lock, C., Odell, E., Castor, D., Toth, R., Rouse, J. (2016) Karyomegalic interstitial nephritis and DNA damage-induced polyploidy in Fan1 nuclease-defective knock-in mice Genes Dev 30 639-644
6   Feeney, L. E., Munoz, I. M., Lachaud, C., Toth, R., Schindler, D., and Rouse, J. (2017) RPA-mediated recruitment of the E3 ligase RFWD3 to DNA inter-strand crosslinks (ICL) is vital for ICL repair and human health. Mol. Cell. In press