論文

査読有り 国際誌
2018年7月

DNA repair processes are critical mediators of p53-dependent tumor suppression.

Nature medicine
  • Ana Janic
  • Liz J Valente
  • Matthew J Wakefield
  • Leon Di Stefano
  • Liz Milla
  • Stephen Wilcox
  • Haoyu Yang
  • Lin Tai
  • Cassandra J Vandenberg
  • Andrew J Kueh
  • Shinsuke Mizutani
  • Margs S Brennan
  • Robyn L Schenk
  • Lisa M Lindqvist
  • Anthony T Papenfuss
  • Liam O'Connor
  • Andreas Strasser
  • Marco J Herold
  • 全て表示

24
7
開始ページ
947
終了ページ
953
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1038/s41591-018-0043-5

It has long been assumed that p53 suppresses tumor development through induction of apoptosis, possibly with contributions by cell cycle arrest and cell senescence1,2. 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 function3-5. 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.

リンク情報
DOI
https://doi.org/10.1038/s41591-018-0043-5
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/29892060
ID情報
  • DOI : 10.1038/s41591-018-0043-5
  • PubMed ID : 29892060

エクスポート
BibTeX RIS