The Molecular Mechanism By Which Glucose Induces DNA Damage Through The P38 MAPK Signaling Pathway

The most important thing for human health is to maintain the stability and integrity of the genome.There is growing evidence that various endogenous and exogenous damage factors damage our DNA.In order to maintain the integrity of the genome,cells have gradually formed a variety of defense mechanisms to reduce the accumulation of DNA damage during the evolutionary process.The DNA damage response mechanism（DDR）is very important to repair DNA damage and maintain the stability and integrity of the genome.High sugar diet will increase the risk of metabolic diseases and cardiovascular and cerebrovascular diseases,accelerate human aging and shorten life span.It has been reported that high glucose in vivo and high glucose in cell culture system can induce oxidative stress and damage DNA integrity.However,little is known about the relationship between high glucose concentration and DNA damage response and repair mechanism.Therefore,revealing the regulatory relationship between high sugar diet and DNA damage repair will help us to understand the harm of high sugar diet to human.In this study,we used Caenorhabditis elegans（C.elegans）as a model to investigate the mechanism of DNA damage induced by high glucose.First,we found that 2% high glucose treatment of nematode larvae resulted in a diapause phenotype in nematode worms.At the same time,high glucose treatment resulted in abnormal nuclear segregation and significantly increased levels of γ-H2 AX,an important marker of DNA damage.Second,high glucose promotes the production of Reactive oxygen species（ROS）in nematode worms,and mediates DNA damage in nematode larvae.Through bioinformatics analysis,we found that transcription factor EGL-44（homologous to mammalian TEAD）downstream of Hippo signaling pathway positively regulates a series of DNA homologous recombination and repair genes.High glucose treatment resulted in the inactivation of EGL-44 by transposition from the nucleus to the cytoplasm.At the same time,we also found that rpa-1 and rad-51,two important proteins involved in DNA homologous recombination repair,were reduced in high glucose treated C.elegans.Functional analysis showed that EGL-44 positively regulated rpa-1 and rad-51 at the transcriptional level.Therefore,high glucose induced intestinal DNA damage in nematode larvae by inhibiting the expression of rpa-1 and rad-51 by inhibiting EGL-44.It has been shown that high glucose activates PMK-1（a homologous protein of mammalian p38 MAPK）,a process that is ROS-dependent.In mammals,p38 MAPK can mediate the exudation of TEAD through phosphorylation by binding to the D-domain of TEAD.Through sequence alignment,we found that the D-domain of EGL-44 was highly conserved with TEAD,suggesting that PMK-1 may have similar functions.In conclusion,our study reveals a novel mechanism of glucose-induced DNA damage,namely glucose activates PMK-1 by increasing ROS production and leads to the inactivation of transcription factor EGL-44 by nucleation.The expression of rpa-1 and rad-51,the target genes of egl-44,was decreased,and eventually DNA damage was found in the intestinal tract of nematode worms.Our study suggests that controlling glucose intake is beneficial for maintaining genomic stability.