RASSF Signalling and DNA Damage: Monitoring the Integrity of the Genome?

Abstract

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.

Figure 1

Cartoon depicting the interactions of RASSF1A and RASSF1C. RASSF1A and RASSF1C share a common C-terminal aminoacid sequence, which includes the ATM phosphorylation site (red asterisk), the RA domain, and the SARAH domain but differs at the N-terminal. RASSF1A has a C1 domain which interacts with MOAP-1 and MDM2. RASSF1C lacks the C1 domain but has an alternative DAXX interaction domain. Serine 131 of RASSF1A has been shown to be mutated from serine (S) to phenylalanine (F). An alanine (A) to Serine (S) polymorphism also exists at the 133 site.

Figure 2

Cartoon depicting DNA damage activated pathways downstream of RASSF family members. RASSF family members, activated by DNA damage, signal through various intermediates (primary interaction: light blue and green [involving RASSF1C or RASSF7]; secondary: orange and tertiary: red) to activate p53, p73, and caspases (purple) to control apoptosis, genome stability, and senescence. Feedback loops exist from caspases and p53 that further activate the pathways and amplify the signal. RASSF1A can also directly sequester MDM2 leading to p53 activation. RASSF1C can transfer DNA damage signals from the nucleus to the cytoplasm by activating JNK signalling. RASSF7 acts as an oncogene inhibiting the activation of JNK.