Binding to WGR Domain by Salidroside Activates PARP1 and Protects Hematopoietic Stem Cells from Oxidative Stress

Abstract

Aims: A component of the base excision repair pathway, poly(ADP-ribose) polymerase-1 (PARP1) functions in multiple cellular processes, including DNA repair and programmed cell death. We previously showed that Salidroside, a phenylpropanoid glycoside isolated from medicinal plants, prevented the loss of hematopoietic stem cells (HSCs) in native mice and rescued HSCs repopulating in transplanted recipients under oxidative stress. The aim of this study was to investigate the mechanism by which PARP1 activation by Salidroside maintains HSCs under oxidative stress. Results: We found that although there were no spontaneous defects in hematopoiesis in Parp1 -/ -mice, oxidative stress compromised the repopulating capacity of Parp1 -/ -HSCs in transplanted recipient mice. A biochemical study using truncated proteins lacking the defined functional domains of PARP1 showed that the tryptophan-glycine-arginine-rich (WGR) domain of PARP1 was critical for Salidroside binding and subsequent PARP1 activation under oxidative stress. Functionally, complementation of Parp1 -/ -HSCs with full-length PARP1 WT , but not the PARP1 R591K mutant in WGR domain restored Salidroside-stimulated PARP1 activation in vitro. Mechanistically, activated PARP1 by Salidroside enhanced the repopulating capacity of the stressed HSCs by accelerating oxidative DNA damage repair. Innovations and Conclusion: Our findings reveal the action of mechanism for Salidroside in PARP1 stimulation and a novel role of PARP1 activation in maintaining HSC function under oxidative stress.

Rhodiola rosea L.: an Herb with Anti-Stress, Anti-Aging, and Immunostimulating Properties for Cancer Chemoprevention

“…Li et al [110] observed that salidroside specifically failed to inhibit H 2 O 2 -induced DNA strand breaks in hematopoietic stem cells (HSCs) from mice with poly(ADP-ribose)polymerase-1 (PARP-1), a component of the base excision repair pathway, deletion, but not those with deficiency in homologous recombination, nonhomologous end-joining, nucleotide excision repair, or fanconi anemia pathway. In addition, they observed that salidroside enhanced the PARP-1 activity to prevent quiescent HSCs from oxidative stress-induced cycling and subsequent exhaustion in native animals and self-renewal defect in transplanted recipients [111]. Further study by the same group demonstrated the binding of salidroside to the tryptophan-glycine-arginine-rich domain of PARP-1[111].…”

“…In addition, they observed that salidroside enhanced the PARP-1 activity to prevent quiescent HSCs from oxidative stress-induced cycling and subsequent exhaustion in native animals and self-renewal defect in transplanted recipients [111]. Further study by the same group demonstrated the binding of salidroside to the tryptophan-glycine-arginine-rich domain of PARP-1[111]. …”

Salidroside improves endothelial function and alleviates atherosclerosis by activating a mitochondria-related AMPK/PI3K/Akt/eNOS pathway

“…A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 6 The collection of human umbilical cords was approved by the Ethics Committee of Tongji Medical…”

“…Previous studies have shown that SAL activates DNA repair enzyme poly (ADP-ribose) polymerase (Parp-1) and protects cells from oxidative stress [5,6]. A recent study has reported that SAL can efficiently decrease atherosclerotic plaque formation in low-density lipoprotein receptor-deficient mice [7], but the mechanism of its anti-atherosclerotic action has not been shown.…”

When Anti-Aging Studies Meet Cancer Chemoprevention: Can Anti-Aging Agent Kill Two Birds with One Blow?

“…Salidroside is the main bioactive compound in Rhodiola rosea extracts. Salidroside prevented the loss of hematopoietic stem cells in mice under oxidative stress via activating DNA repair enzyme poly (ADP-ribose) polymerase-1 (PARP-1) activity [181]. Salidroside also inhibited cancer cell migration and invasion, as well as xenograft tumor growth of human glioma cells in nude mice [182, 183].…”