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.
