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

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.

RNA polymerase III component Rpc9 regulates hematopoietic stem and progenitor cell maintenance in zebrafish

“…The constitutive activation of P53 is harmful for the stemness of HSPCs (Liu et al, 2010;Wang et al, 2011), whereas HSPCs in the p53 mutant are relatively normal (Lotem and Sachs, 1993). Here, we found that the transcript of p53 was specifically increased in the CHT region of rpc9 mutants, mediating HSPC impairments, which is similar to two works reporting that HSPC defects in zebrafish embryos deficient in TopBP1 (topoisomerase II β binding protein 1, involved in DNA replication and DNA damage) or the ribosome protein Rpl11 could be rescued by knockdown of p53 (Danilova et al, 2011;Gao et al, 2015).…”

The emerging role of p53 in stem cells

“…Three recent papers address the issue of how both mouse and human hematopoietic stem and progenitor cells (HSPCs) respond to radiation-induced DD [57][58][59]. These studies indicate that hematopoietic cells can adopt different means of handling DD, depending on their differentiation stage.…”

“…Surprisingly, they also show that DD responses in mouse or human cells follow opposite routes and unravel a different role for p53 in the DD response of HSPCs. Mouse HSPCs (defined as lin À Sca1 + cKit + flk2 À ) have a unique cell intrinsic mechanism that ensures their survival following X-ray treatment and which involves the activation of p53 and its transcriptional target p21 and DNA repair [58,59]. By contrast, human cord blood HSPCs exhibit p53-dependent radiation-induced apoptosis.…”

“…Recently, three elegant studies have highlighted a role for p53 in regulating the competitive selection of stem and progenitor cells (HSPCs following the stress of ionizing radiation (IR) [59][60][61]. After IR, cells with lower levels/ activity of p53 outgrew those with higher levels/activity.…”

p53 Basic C Terminus Regulates p53 Functions through DNA Binding Modulation of Subset of Target Genes

“…Together with the data presented here, these studies allude to the limitations of cell culture based approaches and further stress the need for a more physiological model, such as a transgenic mouse, to study the role of the p53 CTD in vivo. In fact, whereas the C-terminal lysines post-translational modifications originally were shown to be dispensable during embryogenesis and did not significantly affect p53 activity in mouse embryonic fibroblasts (19,20), a recent report shows that these modifications contributes to hematopoietic stem cells homeostasis and confirms the tissue and condition-specific effects of the post-translationally modified C-terminal lysines in vivo (49).…”