Autophagy confers DNA damage repair pathways to protect the hematopoietic system from nuclear radiation injury

Abstract

Autophagy is essentially a metabolic process, but its in vivo role in nuclear radioprotection remains unexplored. We observed that ex vivo autophagy activation reversed the proliferation inhibition, apoptosis, and DNA damage in irradiated hematopoietic cells. In vivo autophagy activation improved bone marrow cellularity following nuclear radiation exposure. In contrast, defective autophagy in the hematopoietic conditional mouse model worsened the hematopoietic injury, reactive oxygen species (ROS) accumulation and DNA damage caused by nuclear radiation exposure. Strikingly, in vivo defective autophagy caused an absence or reduction in regulatory proteins critical to both homologous recombination (HR) and non-homologous end joining (NHEJ) DNA damage repair pathways, as well as a failure to induce these proteins in response to nuclear radiation. In contrast, in vivo autophagy activation increased most of these proteins in hematopoietic cells. DNA damage assays confirmed the role of in vivo autophagy in the resolution of double-stranded DNA breaks in total bone marrow cells as well as bone marrow stem and progenitor cells upon whole body irradiation. Hence, autophagy protects the hematopoietic system against nuclear radiation injury by conferring and intensifying the HR and NHEJ DNA damage repair pathways and by removing ROS and inhibiting apoptosis.

Nuclear localization of Beclin 1 promotes radiation-induced DNA damage repair independent of autophagy

“…This finding suggests that when manipulating cytoplasmic Beclin 1 that is involved in the autophagy pathway in order to explore targeted therapies, the non-autophagy cytoprotective role of Beclin 1 in the nucleus should also be considered. Taken our recent finding that autophagy is radioprotetive37 and the present work on Beclin1 in DNA damage repair independence of autophagy together, combinatory activation of autophagy and upregulation of Beclin 1 may be contributable to a more effective mitigation of radiation injury.…”

“…Recent studies by our team and other groups have suggested that ATG7-dependent autophagy may be linked to the DNA damage repair pathway because inducing the loss of autophagy by deleting the autophagy-essential gene Atg 7 results in the downregulation of certain DSB repair proteins3738. In these studies, the activation of autophagy by rapamycin elevated the levels of DNA repair proteins in both HR and NHEJ pathways, and loss of Atg 7 resulted in a decrease in DSB repair activity37 and an increase in the proteasomal degradation of checkpoint kinase 1, which is a critical factor in HR repair pathway38.…”

“…In these studies, the activation of autophagy by rapamycin elevated the levels of DNA repair proteins in both HR and NHEJ pathways, and loss of Atg 7 resulted in a decrease in DSB repair activity37 and an increase in the proteasomal degradation of checkpoint kinase 1, which is a critical factor in HR repair pathway38. Autophagy is, in essence, a metabolic pathway that involves lysosomal degradation39.…”

Synergistic Ototoxicity of Gentamicin and Low-Dose Irradiation: Molecular Basis and Clinical Significance

“…Repair of double-strand breaks becomes impaired which results in ionizing radiation-induced cell death [Wang et al, 2016[Wang et al, , 2017]. An independent report also showed that defective autophagy caused a reduction in regulatory proteins critical to DNA repair pathways under irradiation stress [Lin et al, 2015]. Based on the results of these studies, it is conceivable that when cochlear cells were exposed to both gentamicin and radiation concurrently, gentamicin-induced perturbation of autophagic flux led to an impairment of DNA repair following radiation damage, and ultimately resulted in enhanced apoptotic cell deaths.…”

A novel bone marrow targeted gadofullerene agent protect against oxidative injury in chemotherapy

“…However, most chemotherapeutic drugs kill the tumor cells and those proliferating cells non-selectively [3,4], so it often leads to serious injury to normal tissues [5][6][7][8][9]. For example, chemotherapy generates a large amount of excess reactive oxygen species (ROS) in the bone marrow that would result in a random damage to the hematopoietic tissues [10,11], leading to serious myelosuppression [12][13][14] as well as severe injury of some normal organs [15,16].…”