Autophagy Promotes the Repair of Radiation-Induced DNA Damage in Bone Marrow Hematopoietic Cells via Enhanced STAT3 Signaling.
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.
a   Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Soochow University School of Medicine, Suzhou 215123, China.
Fei
F
Xu
a   Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Soochow University School of Medicine, Suzhou 215123, China.
Xin
X
Li
a   Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Soochow University School of Medicine, Suzhou 215123, China.
Lili
L
Yan
a   Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Soochow University School of Medicine, Suzhou 215123, China.
Na
N
Yuan
a   Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Soochow University School of Medicine, Suzhou 215123, China.
Yixuan
Y
Fang
a   Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Soochow University School of Medicine, Suzhou 215123, China.
Yan
Y
Cao
a   Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Soochow University School of Medicine, Suzhou 215123, China.
Li
L
Xu
a   Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Soochow University School of Medicine, Suzhou 215123, China.
Xiaoying
X
Zhang
a   Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Soochow University School of Medicine, Suzhou 215123, China.
Lan
L
Xu
a   Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Soochow University School of Medicine, Suzhou 215123, China.
Chaorong
C
Ge
a   Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Soochow University School of Medicine, Suzhou 215123, China.
Ni
N
An
a   Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Soochow University School of Medicine, Suzhou 215123, China.
Gaoyue
G
Jiang
a   Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Soochow University School of Medicine, Suzhou 215123, China.
Jialing
J
Xie
a   Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Soochow University School of Medicine, Suzhou 215123, China.
Han
H
Zhang
a   Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Soochow University School of Medicine, Suzhou 215123, China.
Jiayi
J
Jiang
a   Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Soochow University School of Medicine, Suzhou 215123, China.
Xiaotian
X
Li
a   Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Soochow University School of Medicine, Suzhou 215123, China.
Lei
L
Yao
a   Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Soochow University School of Medicine, Suzhou 215123, China.|b   Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas Medical Sciences, Little Rock, Arkansas 72205.
Suping
S
Zhang
b   Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas Medical Sciences, Little Rock, Arkansas 72205.
Daohong
D
Zhou
a   Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Soochow University School of Medicine, Suzhou 215123, China.
Jianrong
J
Wang
D021581:Active Transport, Cell Nucleus / Q000528:radiation effects; D000818:Animals; D001343:Autophagy / Q000528:radiation effects*; D019313:BRCA1 Protein / Q000235:genetics; D001854:Bone Marrow Cells / Q000166:cytology*; D002467:Cell Nucleus / Q000378:metabolism / Q000528:radiation effects; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects*; D004260:DNA Repair / Q000528:radiation effects*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects*; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D059748:Proteolysis / Q000528:radiation effects; D012097:Repressor Proteins / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000528:radiation effects*; D014158:Transcription, Genetic / Q000528:radiation effects; D000076183:Tripartite Motif-Containing Protein 28
D019313:BRCA1 Protein; D009687:Nuclear Proteins; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; C103190:Trim28 protein, mouse; D000076183:Tripartite Motif-Containing Protein 28