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Tissue regenerative delays and synthetic lethality in adult mice after combined deletion of Atr and Trp53

Nature Genetics volume 41, pages 1144–1149 (2009)Cite this article

Abstract

Trp53 loss of function has previously been shown to rescue tissue maintenance and developmental defects resulting from DNA damage or DNA-repair gene mutations1,2,3,4,5,6,7,8,9,10,11,12. Here, we report that p53 deficiency severely exacerbates tissue degeneration caused by mosaic deletion of the essential genome maintenance regulator Atr. Combined loss of Atr and p53 (Trp53−/−AtrmKO) led to severe defects in hair follicle regeneration, localized inflammation (Mac1+Gr1+ infiltrates), accelerated deterioration of the intestinal epithelium and synthetic lethality in adult mice. Tissue degeneration in Trp53−/−AtrmKO mice was characterized by the accumulation of cells maintaining high levels of DNA damage. Moreover, the elevated frequency of these damaged cells in both progenitor and downstream compartments in Trp53−/−AtrmKO skin coincided with delayed compensatory tissue renewal from residual ATR-expressing cells. Together, our results indicate that the combined loss of Atr and Trp53 in adult mice leads to the accumulation of highly damaged cells, which, consequently, impose a barrier to regeneration from undamaged progenitors.

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Figure 1: Mosaic Atr deletion in adult mice is synthetic lethal with Trp53 deficiency.
Figure 2: Accumulation of damaged cells in the bone marrow and intestines of Trp53−/−AtrmKO mice.
Figure 3: Trp53 deficiency markedly delays hair follicle regeneration following localized Atr deletion in the skin and leads to acute inflammation.
Figure 4: Trp53−/−AtrmKO skin is characterized by the persistent accumulation of γH2AX-positive cells.
Figure 5: p53 is required for efficient compensatory renewal after Atr deletion.

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Acknowledgements

We are indebted to G. Beatty, K. Cimprich, G. Cotsarelis and A. Bhandoola for reagents, protocols and helpful advice, and J. Wang and other members of the AFCRI Histology Core for tissue processing. These studies were supported by the US National Institute on Aging (R01AG027376 and F30AG034027) and the Abramson Family Cancer Research Institute.

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  1. Yaroslava Ruzankina and David W Schoppy: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

    Yaroslava Ruzankina, David W Schoppy, Amma Asare, Carolyn E Clark, Robert H Vonderheide & Eric J Brown

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  1. Yaroslava Ruzankina
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  2. David W Schoppy
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Contributions

Y.R., D.W.S. and E.J.B. designed and interpreted the experiments and wrote the manuscript. Y.R. and D.W.S. performed all of the experiments, with assistance from A.A. (mouse maintenance, qPCR and histological analysis) and C.E.C. and R.H.V. (quantification of Gr1+Mac1+ cell infiltration).

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Correspondence to Eric J Brown.

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Ruzankina, Y., Schoppy, D., Asare, A. et al. Tissue regenerative delays and synthetic lethality in adult mice after combined deletion of Atr and Trp53. Nat Genet 41, 1144–1149 (2009). https://doi.org/10.1038/ng.441

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