Poster Presentation 29th Lorne Cancer Conference 2017

shRNA screens indicate that DNA repair is the process critical for p53-mediated tumour suppression (#179)

Ana Janic 1 , Liz J Valente 2 , Liz Mila 1 , Stephen Wilcox 1 , Lin Tai 1 , Haoyu Yang 1 , Andrew Kueh 1 , Shinsuke Mizutani 1 , Anthony T Papenfuss 1 3 , Liam O'Connor 1 , Marco J Herold 1 , Andreas Strasser 1
  1. Walter and Eliza Hall Institute for Medical Research, Parkville, VIC, Australia
  2. Division of Radiation Oncology- Radiation and Cancer Biology, Stanford University School of Medicine, California, USA
  3. Peter MacCallum Cancer Centre, Parkville, VIC, Australia

It has long been assumed that p53 suppresses tumorigenesis mainly by inducing apoptosis, with possible contributions by cell cycle arrest and cell senescence. This view has, however, been challenged by observations that combined loss of p53-mediated apoptosis, cell cycle arrest and cell senescence does not recapitulate the marked predisposition to spontaneous tumour development seen in p53-deficient mice. We used in vivo shRNA library screens in haematopoietic stem/progenitor cells (HSPCs) to identify p53 target genes that are essential for its tumour suppressive function. This mainly revealed genes implicated in DNA repair (Mlh1, Cav1) but also some involved in cell proliferation (Cav1) or poorly defined functions (Zmat3, Ctsf). Knockdown of Ctsf, Cav1 or Zmat3 promoted lymphoma/leukaemia development only when p53-mediated apoptosis, cell cycle arrest and senescence were also impaired. Remarkably, knockdown of Mlh1 was able to cause lymphoma/leukaemia in a wild type background as potently as knockdown of p53. These findings demonstrate that there is extensive cooperation of several p53-regulated processes to safeguard against tumour development. Importantly, our data suggest that control of DNA repair, dependent on MLH1 and its partners in the DNA mismatch repair, may be the most important tumour suppressive process activated by p53, at least in the haematopoietic compartment.