C78
The role of RASSF1A signalling in the DNA damage response
Garth Hamilton, Karen Yee, Eric O'Neill
Gray Institute for Radiation Oncology and Biology, Oxford, UK
Method
RASSF1A is a tumour suppressor gene that is epigenetically silenced in a wide variety of sporadic human malignancies. While signals that activate RASSF1A downstream pathways are not well understood, there is mounting evidence for stimulation in response to DNA damage. Our aim is to validate the extent to which RASSF1A signalling contributes to an overall DNA damage response and determine if genetic silencing hampers the effectiveness of DNA damaging therapeutics. Moreover, utilising proteomics to identify interacting proteins we are attempting to highlight important regulatory steps in the pathway. Should RASSF1A be an indicator of de-sentivity to DNA damage (e.g. promoter methylation [2] then these regulatory steps could be targetted to improve radiotherapy of RASSF1A silenced tumours.
Results
RASSF1A regulates the interaction of MST2 with its substrate LATS1 [1], in response to DNA damage from ionising radiation. Moreover, this damage signalling regulates specific interactions with RASSF1A and LATS1 with key components that regulate early steps in DNA repair.
Conclusion
A new function for the RASSF1A pathway in tumourigenesis may be the regulation DNA repair.
References
[1] Matallanas D, Romano D, Yee K, Meissl K, Kucerova L, Piazzolla D, Baccarini M, Vass JK, Kolch W, O'Neill E. RASSF1A elicits apoptosis through an MST2 pathway directing proapoptotic transcription by the p73 tumor suppressor protein.Mol Cell. 2007 Sep 21;27(6):962-75.
[2] Dote H, Cerna D, Burgan WE, Carter DJ, Cerra MA, Hollingshead MG, Camphausen K, Tofilon PJ. Enhancement of in vitro and in vivo tumor cell radiosensitivity by the DNA methylation inhibitor zebularine. Clin Cancer Res. 2005 Jun 15;11(12):4571-9.
