ena-STUDY-Walter and Eliza Hall Institute-21-03-2018-05:12:10:446-433
Sensitised in vivo shRNA screens were performed to target p53-regulated genes in E mu-myc mice
It has long been assumed that p53 suppresses tumour development through induction of apoptosis, possibly with contributions by cell cycle arrest and cell senescence1,2. However, combined deficiency in these three processes, unlike loss of p53, does not cause spontaneous tumour development, relaunching the search for the mechanisms that are critical for p53 to suppresses tumorigenesis3-5. To define such mechanisms, we performed sensitised in vivo screens in mice with an shRNA library targeting p53-regulated genes. We found that knockdown of three of the hits, Zmat3, Ctsf and Cav1, promoted lymphoma/leukaemia development only when PUMA and p21, the critical effectors of p53-driven apoptosis, cell cycle arrest and senescence, were also absent. Notably, loss of the DNA repair gene Mlh1, caused lymphoma in a wild-type background and its enforced expression was able to delay tumour development driven by loss of p53. Knockdown of Mlh1, Msh2, Rnf144b, Cav1 and Ddit4, all direct p53 target genes and implicated in DNA repair, accelerated MYC-driven lymphoma development to a similar extent as knockdown of p53. Collectively, these findings demonstrate that extensive functional overlap of several p53-regulated processes safeguards against cancer and that, at least within the haematopoietic compartment, coordination of DNA repair appears to be an important process by which p53 suppresses tumour development.
It has long been assumed that p53 suppresses tumour development through induction of apoptosis, possibly with contributions by cell cycle arrest and cell senescence1,2. However, combined deficiency in these three processes, unlike loss of p53, does not cause spontaneous tumour development, relaunching the search for the mechanisms that are critical for p53 to suppresses tumorigenesis3-5. To define such mechanisms, we performed sensitised in vivo screens in mice with an shRNA library targeting p53-regulated genes. We found that knockdown of three of the hits, Zmat3, Ctsf and Cav1, promoted lymphoma/leukaemia development only when PUMA and p21, the critical effectors of p53-driven apoptosis, cell cycle arrest and senescence, were also absent. Notably, loss of the DNA repair gene Mlh1, caused lymphoma in a wild-type background and its enforced expression was able to delay tumour development driven by loss of p53. Knockdown of Mlh1, Msh2, Rnf144b, Cav1 and Ddit4, all direct p53 target genes and implicated in DNA repair, accelerated MYC-driven lymphoma development to a similar extent as knockdown of p53. Collectively, these findings demonstrate that extensive functional overlap of several p53-regulated processes safeguards against cancer and that, at least within the haematopoietic compartment, coordination of DNA repair appears to be an important process by which p53 suppresses tumour development.