Abstract
Maintenance of genetic stability via proper DNA repair in stem and progenitor cells is essential for the tissue repair and regeneration, while preventing cell transformation after damage. Loss of PUMA dramatically increases the survival of mice after exposure to a lethal dose of ionizing radiation (IR), while without promoting tumorigenesis in the long-term survivors. This finding suggests that PUMA (p53 upregulated modulator of apoptosis) may have a function other than regulates apoptosis. Here, we identify a novel role of PUMA in regulation of DNA repair in embryonic or induced pluripotent stem cells (PSCs) and immortalized hematopoietic progenitor cells (HPCs) after IR. We found that PUMA-deficient PSCs and HPCs exhibited a significant higher double-strand break (DSB) DNA repair activity via Rad51-mediated homologous recombination (HR). This is because PUMA can be associated with early mitotic inhibitor 1 (EMI1) and Rad51 in the cytoplasm to facilitate EMI1-mediated cytoplasmic Rad51 ubiquitination and degradation, thereby inhibiting Rad51 nuclear translocation and HR DNA repair. Our data demonstrate that PUMA acts as a repressor for DSB DNA repair and thus offers a new rationale for therapeutic targeting of PUMA in regenerative cells in the context of DNA damage.
Highlights
Stem cells are undifferentiated cells with the potential of selfrenewal and differentiation into various kinds of cell types during the development and lifetime
We show that PUMA knockout (KO) pluripotent stem cells (PSCs) and hematopoietic progenitor cells (HPCs) underwent enhanced double-strand break (DSB) repair via homologous recombination (HR) and nonhomologous end joining (NHEJ) after exposure to ionizing radiation (IR)
PUMA deficiency increases DNA repair in both PSCs and HPCs following IR γH2AX foci have been widely used as a sensitive indicator for DNA doublestrand break (DSB).[13]
Summary
Stem cells are undifferentiated cells with the potential of selfrenewal and differentiation into various kinds of cell types during the development and lifetime. Because stem and progenitor cells are responsible for the tissue regeneration under homeostatic conditions and after injury, respectively, any mis-repaired DNA damage in these cells can be transmitted to their differentiated progeny, compromising tissue integrity and function.[1]. Inactivation of PUMA provides significant radioprotection at the level of hematopoietic stem cells,[10] thereby conferring striking long-term survival of the exposed mice after lethal dose of IR. And puzzlingly, no increase of hematopoietic malignancies was observed in the long-term survived animals after exposure to a high-dose of IR.[10] These striking and unique phenotypes cannot be explained by the reduced apoptosis in the stem and progenitor cell compartments in the absence of PUMA. Our results demonstrate that PUMA can repress Rad51-mediated HR repair via promoting its ubiquitination by EMI1. Flow cytometry analysis showed that the percent ing genomic instability
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