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Characterizing DNA Repair Processes at Transient and Long-lasting Double-strand DNA Breaks by Immunofluorescence Microscopy
Published on: June 8, 2018
DNA repair processes are critical mediators of p53-dependent tumor suppression
Ana Janic1,2, Liz J Valente1,2,3, Matthew J Wakefield1,4
1Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
Abstract:
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.
Insights
The tumor suppressor p53 uses multiple pathways, including DNA repair, to prevent cancer. Loss of these overlapping functions accelerates tumor development, highlighting DNA repair
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The tumor suppressor protein p53 is traditionally thought to prevent cancer mainly via apoptosis, cell cycle arrest, and senescence.
- Loss of these functions alone does not fully explain tumor development observed upon p53 loss, suggesting other critical mechanisms exist.
Purpose of the Study:
- To identify novel p53-dependent tumor suppression mechanisms beyond apoptosis, cell cycle arrest, and senescence.
- To investigate the role of DNA repair genes in p53-mediated tumor suppression.
Main Methods:
- Utilized in vivo shRNA screens in sensitized genetic backgrounds to identify p53-regulated genes involved in tumor suppression.
- Analyzed the impact of knocking down specific genes (Zmat3, Ctsf, Cav1, Mlh1, Msh2, Rnf144b, Ddit4) on lymphoma/leukemia development.
- Examined the effect of Mlh1 loss and enforced expression on tumor development in p53-deficient settings.
Main Results:
- Knockdown of Zmat3, Ctsf, and Cav1 accelerated lymphoma/leukemia only when key p53 effectors (PUMA, p21) were absent.
- Loss of the DNA repair gene Mlh1 induced lymphoma in wild-type mice, and its expression delayed p53-loss-driven tumors.
- Knockdown of several DNA repair genes (Mlh1, Msh2, Rnf144b, Cav1, Ddit4) accelerated MYC-driven lymphoma development similarly to p53 knockdown.
Conclusions:
- p53 employs a network of overlapping tumor suppressive functions, including DNA repair, to prevent cancer.
- Coordination of DNA repair is a crucial, previously underappreciated mechanism by which p53 suppresses tumor development.
- Understanding these overlapping pathways offers new insights into cancer prevention and therapeutic strategies.
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