DNA repair processes are critical mediators of p53-dependent tumor suppression
- Janic, A; Valente, LJ; Wakefield, MJ; Di Stefano, L; Milla, L; Wilcox, S; Yang, H; Tai, L; Vandenberg, CJ; Kueh, AJ; Mizutani, S; Brennan, MS; Schenk, RL; Lindqvist, LM; Papenfuss, AT; O'Connor, L; Strasser, A; Herold, MJ;
Publication Year 2018-07, Volume 24, Issue #7, Page 947-953
- Journal Title
- Nature Medicine
- Publication Type
- Journal Article
- It has long been assumed that p53 suppresses tumor development through induction of apoptosis, possibly with contributions by cell cycle arrest and cell senescence(1,2). However, combined deficiency in these three processes does not result in spontaneous tumor formation as observed upon loss of p53, suggesting the existence of additional mechanisms that are critical mediators of p53-dependent tumor suppression function(3-5). To define such mechanisms, we performed in vivo shRNA screens targeting p53-regulated genes in sensitized genetic backgrounds. We found that knockdown of Zmat3, Ctsf and Cav1, promoted lymphoma/leukemia 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 tumor development driven by loss of p53. Further examination of direct p53 target genes implicated in DNA repair showed that knockdown of Mlh1, Msh2, Rnf144b, Cav1 and Ddit4 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 coordination of DNA repair appears to be an important process by which p53 suppresses tumor development.
- WEHI Research Division(s)
- Molecular Genetics Of Cancer; Bioinformatics; Systems Biology And Personalised Medicine; Stem Cells And Cancer; Cell Signalling And Cell Death
- PubMed ID
- Publisher's Version
- Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2018-06-26 12:34:43Last Modified: 2018-12-21 09:51:00