Fine-tuning p53 activity through C-terminal modification significantly contributes to HSC homeostasis and mouse radiosensitivity

Yunyuan V. Wang; Mathias Leblanc; Norma Fox; Jian-Hua Mao; Kelsey L. Tinkum; Kurt Krummel; Dannielle Engle; David Piwnica-Worms; Helen Piwnica-Worms; Allan Balmain; Kenneth Kaushansky; Geoffrey M. Wahl

doi:10.1101/gad.2024411

Fine-tuning p53 activity through C-terminal modification significantly contributes to HSC homeostasis and mouse radiosensitivity

¹Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA;
²Department of Medicine, University of California at San Diego, La Jolla, California 92093, USA;
³The Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California 94158, USA;
⁴Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA;
⁵Department of Cell Biology and Physiology, Washington University Medical School, St. Louis, Missouri 63110, USA;
⁶Mallinckrodt Institute of Radiology, Washington University Medical School, St. Louis, Missouri 63110, USA;
⁷The BRIGHT Institute, Washington University Medical School, St. Louis, Missouri 63110, USA;
⁸Department of Developmental Biology, Washington University Medical School, St. Louis, Missouri 63110, USA;
⁹Department of Medicine, Washington University Medical School, St. Louis, Missouri 63110, USA;
¹⁰the Howard Hughes Medical Institute, St. Louis, Missouri 63130, USA

Abstract

Cell cycle regulation in hematopoietic stem cells (HSCs) is tightly controlled during homeostasis and in response to extrinsic stress. p53, a well-known tumor suppressor and transducer of diverse stress signals, has been implicated in maintaining HSC quiescence and self-renewal. However, the mechanisms that control its activity in HSCs, and how p53 activity contributes to HSC cell cycle control, are poorly understood. Here, we use a genetically engineered mouse to show that p53 C-terminal modification is critical for controlling HSC abundance during homeostasis and HSC and progenitor proliferation after irradiation. Preventing p53 C-terminal modification renders mice exquisitely radiosensitive due to defects in HSC/progenitor proliferation, a critical determinant for restoring hematopoiesis after irradiation. We show that fine-tuning the expression levels of the cyclin-dependent kinase inhibitor p21, a p53 target gene, contributes significantly to p53-mediated effects on the hematopoietic system. These results have implications for understanding cell competition in response to stresses involved in stem cell transplantation, recovery from adverse hematologic effects of DNA-damaging cancer therapies, and development of radioprotection strategies.