AIM:To investigate whether Recql5,a DNA helicase that plays an important role in the maintenance of genome integrity,is a tumor suppressor in the gastrointestinal tract in mice.METHODS:We generated cohorts of both Rec...AIM:To investigate whether Recql5,a DNA helicase that plays an important role in the maintenance of genome integrity,is a tumor suppressor in the gastrointestinal tract in mice.METHODS:We generated cohorts of both Recql5-proficient and Recql5-deficient Apcmin/+mice and compared the tumor susceptibility in their gastrointestinal tracts.RESULTS:Recql5 deficiency in Apcmin/+mice resulted in a significant increase in the tumor incidence in both the colon(P=0.0162)and the small intestine(P<0.01).These findings have provided the first genetic evidence for a tumor suppression role of Recql5 in the gastrointestinal tract of mice.Importantly,since mouse Recql5 and human RECQL5 are highly conserved,these findings also suggest that RECQL5 may be a tu-mor suppressor for human colon cancer.CONCLUSION:Recql5 has a tumor suppression role in the mouse gastrointestinal tract.展开更多
AIM: To investigate the effects of Recql5 deficiency on liver injury induced by lipopolysaccharide/D-galactosamine(LPS/D-Gal).METHODS: Liver injury was induced in wild type(WT) or Recql5-deficient mice using LPS/D-Gal...AIM: To investigate the effects of Recql5 deficiency on liver injury induced by lipopolysaccharide/D-galactosamine(LPS/D-Gal).METHODS: Liver injury was induced in wild type(WT) or Recql5-deficient mice using LPS/D-Gal,and assessed by histological,serum transaminases,and mortality analyses. Hepatocellular apoptosis was quantified by transferase d UTP nick end labeling assay and Westernblot analysis of cleaved caspase-3. Liver inflammatory chemokine and cytochrome P450 expression was analyzed by quantitative reverse transcription-PCR. Neutrophil infiltration was evaluated by myeloperoxidase activity. Expression and phosphorylation of ERK,JNK,p65,and H2 A.X was determined by Western blot. Oxidative stress was evaluated by measuring malondialdehyde production and nitric oxide synthase,superoxide dismutase,glutathione peroxidase,catalase,and glutathione reductase activity.RESULTS: following LPS/D-Gal exposure,Recql5-deficient mice exhibited enhanced liver injury,as evidenced by more severe hepatic hemorrhage,higher serum aspartate transaminase and alanine transaminase levels,and lower survival rate. As compared to WT mice,Recql5-deficient mice showed an increased number of apoptotic hepatocytes and higher cleaved caspase-3 levels. Recql5-deficient mice exhibited increased DNA damage,as evidenced by increased γ-H2 A.X levels. Inflammatory cytokine levels,neutrophil infiltration,and ERK phosphorylation were also significantly increased in the knockout mice. Additionally,Recql5-deficicent mice exhibited increased malondialdehyde production and elevated inducible nitric oxide synthase,superoxide dismutase,glutathione peroxidase,catalase,and glutathione reductase activity,indicative of enhanced oxidative stress. Moreover,CYP450 expression was significantly downregulated in Recql5-deficient mice after LPS/D-Gal treatment.CONCLUSION: Recql5 protects the liver against LPS/D-Gal-induced injury through suppression of hepatocyte apoptosis and oxidative stress and modulation of CYP450 expression.展开更多
Deficiencies in DNA damage response and repair not only can result in genome instability and cancer predisposition,but also can render the cancer cells intrinsically more vulnerable to certain types of DNA damage insu...Deficiencies in DNA damage response and repair not only can result in genome instability and cancer predisposition,but also can render the cancer cells intrinsically more vulnerable to certain types of DNA damage insults.Particularly,replication stress is both a hallmark of human cancers and a common instigator for genome instability and cell death.Here,we review our work based on the genetic knockout studies on Blm and Recql5,two members of the mammalian RecQ helicase family.These studies have uncovered a unique partnership between these two helicases in the implementation of proper mitigation strategies under different circum-stances to promote DNA replication and cell survival and suppress genome instability and cancer.In particular,current studies have revealed the presence of a novel Recql5/RECQL5-dependent mechanism for suppressing replication fork collapse in response to global replication fork stalling following exposure to camptothecin(CPT),a topoisomerase I inhibitor,and a potent inhibitor of DNA replication.The unique partnership between Blm and Recql5 in coping with the challenge imposed by replication stress is discussed.In addition,given that irinotecan and topotecan,two CPT derivatives,are currently used in clinic for treating human cancer patients with very promising results,the potential implication of the new findings from these studies in anticancer treatments is also discussed.展开更多
基金Supported by Grants RO1 CA88939,P20 CA103736 from the US National Institutes of HealthSearle Scholar Award 01-E-109 from the Searle Scholar Program
文摘AIM:To investigate whether Recql5,a DNA helicase that plays an important role in the maintenance of genome integrity,is a tumor suppressor in the gastrointestinal tract in mice.METHODS:We generated cohorts of both Recql5-proficient and Recql5-deficient Apcmin/+mice and compared the tumor susceptibility in their gastrointestinal tracts.RESULTS:Recql5 deficiency in Apcmin/+mice resulted in a significant increase in the tumor incidence in both the colon(P=0.0162)and the small intestine(P<0.01).These findings have provided the first genetic evidence for a tumor suppression role of Recql5 in the gastrointestinal tract of mice.Importantly,since mouse Recql5 and human RECQL5 are highly conserved,these findings also suggest that RECQL5 may be a tu-mor suppressor for human colon cancer.CONCLUSION:Recql5 has a tumor suppression role in the mouse gastrointestinal tract.
基金Supported by National Natural Science Foundation of China,No.81101472 and No.81472556(to Liao W),and No.81372490(to Lu X)Zhejiang Provincial Natural Science Foundation,No.LZ14H160003(to Lu X)+2 种基金Zhejiang Provincial Program for the Cultivation of High-Level Innovative Health Talents(to Lu X)National Basic Research Program of China(973 Project),No.2011CB504603Wenzhou Municipal Science and Technology Bureau Foundation,No.Y20110090(to Li H)
文摘AIM: To investigate the effects of Recql5 deficiency on liver injury induced by lipopolysaccharide/D-galactosamine(LPS/D-Gal).METHODS: Liver injury was induced in wild type(WT) or Recql5-deficient mice using LPS/D-Gal,and assessed by histological,serum transaminases,and mortality analyses. Hepatocellular apoptosis was quantified by transferase d UTP nick end labeling assay and Westernblot analysis of cleaved caspase-3. Liver inflammatory chemokine and cytochrome P450 expression was analyzed by quantitative reverse transcription-PCR. Neutrophil infiltration was evaluated by myeloperoxidase activity. Expression and phosphorylation of ERK,JNK,p65,and H2 A.X was determined by Western blot. Oxidative stress was evaluated by measuring malondialdehyde production and nitric oxide synthase,superoxide dismutase,glutathione peroxidase,catalase,and glutathione reductase activity.RESULTS: following LPS/D-Gal exposure,Recql5-deficient mice exhibited enhanced liver injury,as evidenced by more severe hepatic hemorrhage,higher serum aspartate transaminase and alanine transaminase levels,and lower survival rate. As compared to WT mice,Recql5-deficient mice showed an increased number of apoptotic hepatocytes and higher cleaved caspase-3 levels. Recql5-deficient mice exhibited increased DNA damage,as evidenced by increased γ-H2 A.X levels. Inflammatory cytokine levels,neutrophil infiltration,and ERK phosphorylation were also significantly increased in the knockout mice. Additionally,Recql5-deficicent mice exhibited increased malondialdehyde production and elevated inducible nitric oxide synthase,superoxide dismutase,glutathione peroxidase,catalase,and glutathione reductase activity,indicative of enhanced oxidative stress. Moreover,CYP450 expression was significantly downregulated in Recql5-deficient mice after LPS/D-Gal treatment.CONCLUSION: Recql5 protects the liver against LPS/D-Gal-induced injury through suppression of hepatocyte apoptosis and oxidative stress and modulation of CYP450 expression.
文摘Deficiencies in DNA damage response and repair not only can result in genome instability and cancer predisposition,but also can render the cancer cells intrinsically more vulnerable to certain types of DNA damage insults.Particularly,replication stress is both a hallmark of human cancers and a common instigator for genome instability and cell death.Here,we review our work based on the genetic knockout studies on Blm and Recql5,two members of the mammalian RecQ helicase family.These studies have uncovered a unique partnership between these two helicases in the implementation of proper mitigation strategies under different circum-stances to promote DNA replication and cell survival and suppress genome instability and cancer.In particular,current studies have revealed the presence of a novel Recql5/RECQL5-dependent mechanism for suppressing replication fork collapse in response to global replication fork stalling following exposure to camptothecin(CPT),a topoisomerase I inhibitor,and a potent inhibitor of DNA replication.The unique partnership between Blm and Recql5 in coping with the challenge imposed by replication stress is discussed.In addition,given that irinotecan and topotecan,two CPT derivatives,are currently used in clinic for treating human cancer patients with very promising results,the potential implication of the new findings from these studies in anticancer treatments is also discussed.
