Mechanisms of DNA interstrand crosslink repair in humans. (360G-Wellcome-210640_Z_18_Z)

My research is focused on uncovering the molecular mechanisms of DNA interstrand crosslink (ICL) repair in humans. Disruption of the underlying DNA-repair pathway causes Fanconi Anemia (FA), with serious cancer susceptibility. Also, ICL-forming drugs are used therapeutically in non-FA cancer patients, however resistance is a major problem. Targeting the FA-pathway could allow clinicians to treat these patients. A key and fundamental event in the FA-pathway is the recruitment of repair proteins to ICLs. Specific and timely recruitment is essential for accurate repair. We have recently discovered proteins specifically detecting ICLs and we have obtained the cryo-EM structure of other ICL-repair proteins. My aim over the next five years is to advance the field further by uncovering mechanistically how repair factors are activated and recruited to ICLs at the single-molecule level. We will: 1) Dissect the mechanism of initial recruitment of repair factors to ICLs. 2) Uncover functions of identified proteins in FANCD2-complexes in ICL-repair. 3) Determine roles of novel phosphorylation sites on FANCD2/FANCI. 4) Elucidate mechanism of FANCD2/FANCI activation. Addressing these central questions will not only greatly advance our understanding of ICL-repair, but will also likely enhance our understanding of other DNA repair pathways utilizing analogous mechanisms.