Dr Stewart

One unrepaired DNA DSB is sufficient to kill a cell. The potentially deleterious nature of this lesion highlights the importance of the cellular pathways involved in repairing this type of damage. Defects in this pathway have been identified in human syndromes, which typically exhibit chromosomal instability and a predisposition to developing cancer.

A family of proteins, termed mediators or adaptors, have recently been shown to play an important function in the cellular response to DNA DSBs. This family comprises a number of proteins which typically contain two or more BRCT domains e.g. BRCA1, 53BP1, MDC1, Claspin, TopBP1, PTIP.

Our group was pivotal in the identification of MDC1 as a key regulator of DNA DSB repair and cell cycle checkpoint activation.

MDC1 functions as a molecular clamp that recruits and holds DNA repair and checkpoint proteins at the sites of DNA damage. Loss of this protein results in genomic instability and cell cycle checkpoint defects.

Our group aims to further characterise the role of MDC1 and its binding partners e.g. 53BP1, BRCA1, Nbs1 during the cellular response to different types of DNA damage. Furthermore we are also interested in how loss of these proteins might contribute to human disease and tumourigenesis.

Dynamic relocolisation of MDC1 protein (green fluorescence) to sites of DNA double strand breaks to form foci within nuclei of cells following exposure to 3Gy of ionising radiation.

• Stewart GS, et al. (1999). The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder. Cell 99: 577-587
• Stewart GS, et al (2003). MDC1 is a mediator of the mammalian DNA damage checkpoint. Nature 421: 961-6.
• Lin SY, et al (2004) Human Claspin works with BRCA1 to both positively and negatively regulate cell proliferation. Proc Natl Acad Sci USA 101: 6484-9.