Tumour suppression through maintenance of genomic integrity. - ATR-RASSF1A-BRCA2 signalling at stalled replication forks

S104 Cancer Sciences
Medical and Dental Sciences
Tuesday 24th June 2014 (13:00-14:00)
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For further information please contact the seminar host, Dr Daniel Tennant E: D.Tennant@bham.ac.uk T:+44(0)121 414 8651 or Pauline Goddard E: P.N.Goddard@bham.ac.uk T:+44(0)121 414 7144

 "Tumour suppression through maintenance of genomic integrity.”  ATR-RASSF1A-BRCA2 signalling at stalled replication forks

Dr Eric O’Neill, Cancer Research UK Oxford Institute, University of Oxford


By interrogating signal transduction pathways, our main aim is to understand how cancers initiate in response to oncogenic signaling and/or loss of tumour suppressor genes. Currently we are working to uncover the reason for prognostic significance behind one the most frequently inactivated tumour suppressors in all human malignancies, RASSF1A. In doing so we have uncovered epigenetic loss of RASSF1A results in deregulation of a number of pathways involved in tumourigenesis, most notably the hippo pathway. More recently we have found that RASSF1A signalling also controls BRCA2 mediated protection of stalled replication fork in response to ATR signalling. We have also identified a single polymorphic variant in the RASSF1 gene that fails to respond to ATR, resulting in unstable forks, genomic instability and widespread predisposition to cancer. Moreover, epigenetic silencing of RASSF1A results in BRCA2-like defects and may generate frequent ‘BRCAness’ in tumours, potentially explaining the correlation with poor outcome through promoting tumours with increased genomic instability