Mediator of DNA Damage Checkpoint 1 (MDC1) is a 2089 amino acid protein with critical functions in DSB repair. In interphase MDC1 promotes both non-homologous end joining (NHEJ) and homologous recombination (HR) by binding to phosphorylated H2AX and facilitating a ubiquitin signaling cascade on chromatin by the E3 ubiquitin ligases RNF8 and RNF168. In addition to several well-described domains, MDC1 also possesses a large, intrinsically disordered region consisting of 13 imperfect repeats of 41 amino acids known as the PST repeat region whose function is poorly understood. Using live-cell single-molecule imaging, we recently found that MDC1 is constitutively tethered to chromatin by its intrinsically disordered PST repeat region even in the absence of DNA damage.  The goals of this project are to understand the mechanistic basis and define the functional significance of the PST repeat-chromatin interaction in the context of DSB repair. 

Mitosis is an essential process where genetic material is equally segregated to produce two identical daughter cells. Despite being especially vulnerable to the potential consequences of DNA DSB breaks, both major DSB repair pathways (HR and NHEJ) are suppressed during mitosis. Two mechanisms of mitotic DSB repair were recently described including DSB tethering by MDC1-TOPBP1-CIP2A and Microhomology-mediated end joining (MMEJ) mediated by Rhino and Polθ. As emerging guardians of genome stability, these pathways offer promising opportunities to discover new biology and reveal new targets for cancer therapy.