Base excision repair （BER） is an evolutionarily conserved process for maintaining genomic integrity by eliminating several dozen damaged （oxidized or aikylated） or inappropriate bases that are generated endogenous...Base excision repair （BER） is an evolutionarily conserved process for maintaining genomic integrity by eliminating several dozen damaged （oxidized or aikylated） or inappropriate bases that are generated endogenously or induced by genotoxicants, predominantly, reactive oxygen species （ROS）. BER involves 4-5 steps starting with base excision by a DNA glycosylase, followed by a common pathway usually involving an AP-endonuclease （APE） to generate 3＇ OH terminus at the damage site, followed by repair synthesis with a DNA polymerase and nick sealing by a DNA iigase. This pathway is also responsible for repairing DNA single-strand breaks with blocked termini directly generated by ROS. Nearly all glycosylases, far fewer than their substrate lesions particularly for oxidized bases, have broad and overlapping substrate range, and could serve as back-up enzymes in vivo. In contrast, mammalian cells encode only one APE, APEI, unlike two APEs in lower organisms. In spite of overall similarity, BER with distinct subpathways in the mammals is more complex than in E. coli. The glycosylases form complexes with downstream proteins to carry out efficient repair via distinct subpathways one of which, responsible for repair of strand breaks with 3＇ phosphate termini generated by the NEIL family glycosylases or by ROS, requires the phosphatase activity of polynucleotide kinase instead of APE1. Different complexes may utilize distinct DNA polymerases and iigases. Mammalian glycosylases have nonconserved extensions at one of the termini, dispensable for enzymatic activity but needed for interaction with other BER and non-BER proteins for complex formation and organeile targeting. The mammalian enzymes are sometimes covalently modified which may affect activity and complex formation. The focus of this review is on the early steps in mammalian BER for oxidized damage.展开更多
BACKGROUND As the malignant tumor,pancreatic cancer with a meager 5-years survival rate has been widely concerning.However,the molecular mechanisms that result in malignant transformation of pancreatic cells remain el...BACKGROUND As the malignant tumor,pancreatic cancer with a meager 5-years survival rate has been widely concerning.However,the molecular mechanisms that result in malignant transformation of pancreatic cells remain elusive.AIM To investigate the gene expression profiles in normal or malignant transformed pancreas development.METHODS MaSigPro and ANOVA were performed on two pancreas development datasets downloaded from the Gene Expression Omnibus database.Six pancreatic cancer datasets collected from TCGA database were used to establish differentially expressed genes related to pancreas development and pancreatic cancer.Moreover,gene clusters with highly similar interpretation patterns between pancreas development and pancreatic cancer progression were established by self-organizing map and singular value decomposition.Additionally,the hypergeometric test was performed to compare the corresponding interpretation patterns.Abnormal regions of metabolic pathway were analyzed using the Subpathway-GM method.RESULTS This study established the continuously upregulated and downregulated genes at different stages in pancreas development and progression of pancreatic cancer.Through analysis of the differentially expressed genes,we established the inverse and consistent direction development-cancer pattern associations.Based on the application of the Subpathway-GM analysis,we established 17 significant metabolic sub-pathways that were closely associated with pancreatic cancer.Of note,the most significant metabolites sub-pathway was related to glycerophospholipid metabolism.CONCLUSION The inverse and consistent direction development-cancer pattern associations were established.There was a significant correlation in the inverse patterns,but not consistent direction patterns.展开更多
文摘Base excision repair （BER） is an evolutionarily conserved process for maintaining genomic integrity by eliminating several dozen damaged （oxidized or aikylated） or inappropriate bases that are generated endogenously or induced by genotoxicants, predominantly, reactive oxygen species （ROS）. BER involves 4-5 steps starting with base excision by a DNA glycosylase, followed by a common pathway usually involving an AP-endonuclease （APE） to generate 3＇ OH terminus at the damage site, followed by repair synthesis with a DNA polymerase and nick sealing by a DNA iigase. This pathway is also responsible for repairing DNA single-strand breaks with blocked termini directly generated by ROS. Nearly all glycosylases, far fewer than their substrate lesions particularly for oxidized bases, have broad and overlapping substrate range, and could serve as back-up enzymes in vivo. In contrast, mammalian cells encode only one APE, APEI, unlike two APEs in lower organisms. In spite of overall similarity, BER with distinct subpathways in the mammals is more complex than in E. coli. The glycosylases form complexes with downstream proteins to carry out efficient repair via distinct subpathways one of which, responsible for repair of strand breaks with 3＇ phosphate termini generated by the NEIL family glycosylases or by ROS, requires the phosphatase activity of polynucleotide kinase instead of APE1. Different complexes may utilize distinct DNA polymerases and iigases. Mammalian glycosylases have nonconserved extensions at one of the termini, dispensable for enzymatic activity but needed for interaction with other BER and non-BER proteins for complex formation and organeile targeting. The mammalian enzymes are sometimes covalently modified which may affect activity and complex formation. The focus of this review is on the early steps in mammalian BER for oxidized damage.
文摘BACKGROUND As the malignant tumor,pancreatic cancer with a meager 5-years survival rate has been widely concerning.However,the molecular mechanisms that result in malignant transformation of pancreatic cells remain elusive.AIM To investigate the gene expression profiles in normal or malignant transformed pancreas development.METHODS MaSigPro and ANOVA were performed on two pancreas development datasets downloaded from the Gene Expression Omnibus database.Six pancreatic cancer datasets collected from TCGA database were used to establish differentially expressed genes related to pancreas development and pancreatic cancer.Moreover,gene clusters with highly similar interpretation patterns between pancreas development and pancreatic cancer progression were established by self-organizing map and singular value decomposition.Additionally,the hypergeometric test was performed to compare the corresponding interpretation patterns.Abnormal regions of metabolic pathway were analyzed using the Subpathway-GM method.RESULTS This study established the continuously upregulated and downregulated genes at different stages in pancreas development and progression of pancreatic cancer.Through analysis of the differentially expressed genes,we established the inverse and consistent direction development-cancer pattern associations.Based on the application of the Subpathway-GM analysis,we established 17 significant metabolic sub-pathways that were closely associated with pancreatic cancer.Of note,the most significant metabolites sub-pathway was related to glycerophospholipid metabolism.CONCLUSION The inverse and consistent direction development-cancer pattern associations were established.There was a significant correlation in the inverse patterns,but not consistent direction patterns.
