Novel isoforms & functions of the S. pombe Rad9 checkpoint protein

• Main Author: Janes, Simon
• Published: Bangor University 2012
• Subjects: 616.994042
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.568804

Cancer is of paramount medical concern as an increasingly major contributor of disease-related fatalities of significant prevalence - particularly in the context of current statisticaLlstochastical epidemiological studies which predict that one in three people will contract cancer at some stage of their lives, whilst one in four of these patients will die as a consequence of their particular neoplastic-associated condition. The human Rad9 protein exists in two full-length isoforms (termed Rad9A and Rad9B) whose respective differentially-elevated levels and related expression profiles are distinctive for specific tumour cell tissue types. Most known functions of the DNA damage response protein Rad9 are executed via the well- characterised Rad9-Rad l-Hus 1 ("9-1-1") protein complex, which is loaded onto chromatin in close vicinity to DNA lesion sites. The chromatin-loaded "9-1-1" complex functions as both a DNA damage "sliding-clamp" sensor and a recruitment platform which modulates and co-ordinates the activities of a wide variety of different proteins implicated in cell cycle checkpoint signalling, steroidal nuclear receptor signalling, protein chaperoning and DNA repair - via associative protein-protein interactions with the C-terminal tail domain of the Rad9 sub-unit. This toroidal, heterotrimeric "9-1-1" DNA sliding-clamp complex is highly conserved and its recently resolved crystal structure shows a functional similarity to the homotrimeric PCNA DNA sliding-clamp complex.