Autophagy Promotes the Repair of Radiation-Induced DNA Damage in Bone Marrow Hematopoietic Cells via Enhanced STAT3 Signaling

Abstract

Autophagy protects hematopoietic cells from radiation damage in part by promoting DNA damage repair. However, the molecular mechanisms by which autophagy regulates DNA damage repair remain largely elusive. Here, we report that this radioprotective effect of autophagy depends on STAT3 signaling in murine bone marrow mononuclear cells (BM-MNCs). Specifically, we found that STAT3 activation and nuclear translocation in BM-MNCs were increased by activation of autophagy with an mTOR inhibitor and decreased by knockout of the autophagy gene Atg7. The autophagic regulation of STAT3 activation is likely mediated by induction of KAP1 degradation, because we showed that KAP1 directly interacted with STAT3 in the cytoplasm and knockdown of KAP1 increased the phosphorylation and nuclear translocation of STAT3. Subsequently, activated STAT3 transcriptionally upregulated the expression of BRCA1, which increased the ability of BM-MNCs to repair radiation-induced DNA damage. This novel finding that activation of autophagy can promote DNA damage repair in BM-MNCs via the ATG-KAP1-STAT3-BRCA1 pathway suggests that autophagy plays an important role in maintaining genomic integrity of BM-MNCs and its activation may confer protection of BM-MNCs against radiation-induced genotoxic stress.

BIRC5/Survivin is a novel ATG12–ATG5 conjugate interactor and an autophagy-induced DNA damage suppressor in human cancer and mouse embryonic fibroblast cells

“…A possible reason for having BIRC5 to suppress and to maintain autophagy at certain levels in cells under "non-stressed conditions" is that hyperactivation of autophagy can cause excessive "self-digestion" and genomic instability, which may lead to cell death. Despite upregulation of autophagy has widely been shown to promote DNA repair in cells treated with different DNA damaging agents [48][49][50], other studies revealed that excessive autophagy could induce genomic instability in cancer cells. For example, excessive autophagy has been shown to decrease the activity of ribonucleotide reductase and the production of deoxyribonucleoside triphosphates (dNTPs), leading to the induction of genomic instability in human cancer cells [51,52].…”

Effect of Differential Expression of Genes Induced by Radiation Therapy In Cancer-associated fibroblasts Cell on Patients' Prognosis

“…Radiation therapy acts on the body, causing damage to biological macromolecules such as DNA. The body will initiate damage repair responses by regulating the expression of a series of genes, induce cell cycle arrest, and promote DNA repair and regulate cell proliferation [15][16]. Of course, high-dose radiation therapy will seriously damage the tissue structure of cells, inhibit the expression of many functional genes, cause cell DNA replication and repair defects, cell cycle transition disorders, and cell maturation disorders, etc.…”

Autophagy Roles in the Modulation of DNA Repair Pathways

“…As a degradative process, autophagy can mediate direct degradation of molecules involved in DDR. Thus, autophagy protects bone marrow hematopoietic cells against radiation-induced genotoxic stress by directly targeting the KAP1 protein, a corepressor for the Kruppel-associated box-domain-containing zinc-finger proteins, for degradation [ 94 , 95 ]. Also, in response to DNA damage, ATM kinase phosphorylates KAP1, driving heterochromatin relaxation and repair [ 96 , 97 ].…”

“…Also, in response to DNA damage, ATM kinase phosphorylates KAP1, driving heterochromatin relaxation and repair [ 96 , 97 ]. Moreover, KAP1 is a repressor of STAT3 (signal transducer and activator of transcription 3) activation [ 94 , 95 ]. Hence, autophagy promotes repair of radiation-induced DNA damage through STAT3-mediated transcriptional up-regulation of BRCA1, a pleotropic DDR protein that functions in both checkpoint activation and DNA repair, mainly in DSB removal through HR ( Figure 3 A) [ 94 , 98 ].…”