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.

Rouse Lab

People

Laura Feeney | PhD Student
Rathan Jadav | Postdoctoral Researcher
Taran Khanam | Postdoctoral Researcher
Michael Morgan | PhD Student
Ivan M. Muñoz | Postdoctoral Researcher
Maithili Shroff | Marie Curie Funded Early Stage Researcher
Meghan Slean | Postdoctoral Researcher
Florian Weiland | Postdoctoral Researcher

Selected Publications

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
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
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
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
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
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