Flash Talk & Poster Presentation 30th Lorne Cancer Conference 2018

Coordination Of DNA Repair Is Critical For P53-Mediated Tumour Suppression (#109)

Ana Janic 1 , Liz Valente , Matthew Wakefield , Liz Milla , Stephen Wilcox , Cassandra Vandenberg , Leon Di Stefano , Margs Brennan , Robyn Schenk , Anthony Papenfuss , Liam O’Connor , Marco Herold , Andreas Strasser
  1. Walter and Eliza Hall Institute for Medical Research, Parkville, VIC, Australia

The transcription factor p53 is lost or mutated in ~50% of human cancers but it remains unclear which of the diverse processes it regulates mediate tumour suppression. It has long been assumed that induction of apoptosis, cell cycle arrest and cell senescence are critical. This view was, however, overturned by observations that combined loss of p53-driven apoptosis, cell cycle arrest and cell senescence does not recapitulate the 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 whose knock-down can promote leukaemia/lymphoma development. These screens were sensitised by loss of PUMA and p21, the essential mediators of p53-driven apoptosis and cell cycle arrest/senescence, respectively. This screen identified genes involved in DNA repair (Mlh1), cell proliferation (Cav1) and some with poorly defined functions (Zmat3, Ctsf). Knockdown of most validated hits promoted lymphoma/leukaemia development only when PUMA and p21 were also absent, but knockdown of Mlh1 caused lymphoma/leukaemia in a wild-type background. Remarkably, knockdown of several p53 target genes implicated in DNA repair, including Mlh1, Msh2, Polk, Rnf144b, Ddit4, FancC accelerated MYC-driven lymphomagenesis to a similar extent as knockdown of p53 itself. These findings demonstrate that extensive functional overlap of several p53-regulated processes protects against cancer and that (at least within the haematopoietic compartment) coordination of DNA repair appears to be the most important process by which p53 suppresses tumour development.