%0 Journal Article
%T RASSF Signalling and DNA Damage: Monitoring the Integrity of the Genome?
%A Simon F. Scrace
%A Eric O'Neill
%J Molecular Biology International
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/141732
%X The RASSF family of proteins has been extensively studied in terms of their genetics, structure and function. One of the functions that has been increasingly studied is the role of the RASSF proteins in the DNA damage response. Surprisingly, this research, which encompasses both the classical and N-terminal RASSF proteins, has revealed an involvement of the RASSFs in oncogenic pathways as well as the more familiar tumour suppressor pathways usually associated with the RASSF family members. The most studied protein with respect to DNA damage is RASSF1A, which has been shown, not only to be activated by ATM, a major regulator of the DNA damage response, but also to bind to and activate a number of different pathways which all lead to and feedback from the guardian of the genome, p53. In this review we discuss the latest research linking the RASSF proteins to DNA damage signalling and maintenance of genomic integrity and look at how this knowledge is being utilised in the clinic to enhance the effectiveness of traditional cancer therapies such as radiotherapy. 1. Introduction RASSF proteins were originally designated on the basis of sequence homology to domains that associate with Ras-like small GTP-binding proteins. These domains are known as Ras association (RA) domains [RalGDS (Ral guanine nucleotide dissociation stimulator)/AF6 (ALL-1 fusion partner from chromosome 6)] and are distinct from Ras-binding domains (RBD) which bind an alternative set of Ras effectors [1, 2]. Ras belongs to a family of small G-proteins that are ubiquitously expressed and oscillate between an inactive, GDP-bound state, and an active, GTP-bound state, in response to diverse cellular signals. Various GTP-bound Ras-like proteins bind effector proteins to mediate distinct biological responses. There are 150 Ras-like proteins encoded in the human genome which can be grouped by homology or functionality, as being similar to Ras, Rho, Rab, Arf (ADP-ribosylation factor), or Ran. While originally suggested to associate with Ras [3], the RASSF family has a differential affinity for Ras-like GTPases, with NORE1 (RAPL/RASSF5) displaying a much greater affinity for the closely related Ras homolog, Rap1B, than H-Ras itself [4]. The RA domain of RASSF1 associates with K-Ras, rather than H-Ras or N-Ras and is also described to associate with Ran [5, 6]. There are now 10 members in the RASSF family (RASSF1-10) subdivided into two distinct subgroups, the classical RASSF proteins (RASSF1-6) and the N-terminal RASSF proteins (RASSF7-10) based on the location of the RA domain [7]. Little is known
%U http://www.hindawi.com/journals/mbi/2012/141732/