Cancer refers to a diverse collection of diseases characterized by several well-established hallmarks,including the abilities to sustain proliferative signaling,evade growth suppressors,activate invasion and metastasi...Cancer refers to a diverse collection of diseases characterized by several well-established hallmarks,including the abilities to sustain proliferative signaling,evade growth suppressors,activate invasion and metastasis,enable replicative immortality,induce angiogenesis,and resist cell death1.Historically,genetic alterations(deletions,point mutations,and translocations)were thought to be the basis for tumor formation via the inactivation of tumor suppressors and activation of oncogenes.展开更多
DNA is constantly exposed to a wide array of genotoxic agents, generating a variety of forms of DNA damage. DNA-protein crosslinks(DPCs)—the covalent linkage of proteins with a DNA strand—are one of the most deleter...DNA is constantly exposed to a wide array of genotoxic agents, generating a variety of forms of DNA damage. DNA-protein crosslinks(DPCs)—the covalent linkage of proteins with a DNA strand—are one of the most deleterious and understudied forms of DNA damage, posing as steric blockades to transcription and replication. If not properly repaired, these lesions can lead to mutations, genomic instability, and cell death. DPCs can be induced endogenously or through environmental carcinogens and chemotherapeutic agents. Endogenously, DPCs are commonly derived through reactions with aldehydes, as well as through trapping of various enzymatic intermediates onto the DNA. Proteolytic cleavage of the protein moiety of a DPC is a general strategy for removing the lesion. This can be accomplished through a DPC-specific protease and and/or proteasome-mediated degradation.Nucleotide excision repair and homologous recombination are each involved in repairing DPCs, with their respective roles likely dependent on the nature and size of the adduct. The Fanconi anemia pathway may also have a role in processing DPC repair intermediates. In this review, we discuss how these lesions are formed, strategies and mechanisms for their removal, and diseases associated with defective DPC repair.展开更多
Dear Editor,Accumulating evidence suggests that dysregulated lysosomal membrane proteins,including vacuolar ATPase(v-ATPase)and the mammalian target of rapamycin(mTOR),are involved in tumorigenesis[1].Therefore,lysoso...Dear Editor,Accumulating evidence suggests that dysregulated lysosomal membrane proteins,including vacuolar ATPase(v-ATPase)and the mammalian target of rapamycin(mTOR),are involved in tumorigenesis[1].Therefore,lysosomal proteins were proposed as potential therapeutic targets in cancer[1].As one of the lysosome-related signaling pathways,mTOR signaling regulates cell proliferation,survival,motility,and metabolism[2].SincemTOR signaling activation promotes tumorigenesis,mTOR inhibitors(mTORi),AZD8055[3],MLN0128[4],and Rapalink-1(the latest third-generation mTORi)[4],have been applied to several cancers.However,the limitations of mTORi include drug resistance and the lack of biomarkers.展开更多
Immunodeficiency,centromeric instability,and facial anomalies(ICF)syndrome is a rare autosomal recessive disorder characterized by DNA hypomethylation and antibody deficiency.It is caused by mutations in DNMT3B,ZBTB24...Immunodeficiency,centromeric instability,and facial anomalies(ICF)syndrome is a rare autosomal recessive disorder characterized by DNA hypomethylation and antibody deficiency.It is caused by mutations in DNMT3B,ZBTB24,CDCA7,or HELLS.While progress has been made in elucidating the roles of these genes in regulating DNA methylation,little is known about the pathogenesis of the life-threatening hypogammaglobulinemia phenotype.Here,we show that mice deficient in Zbtb24 in the hematopoietic lineage recapitulate the major clinical features of patients with ICF syndrome.Specifically,Vav-Cre-mediated ablation of Zbtb24 does not affect lymphocyte development but results in reduced plasma cells and low levels of IgM,IgG1,and IgA.Zbtb24-deficient mice are hyper and hypo-responsive to T-dependent and T-independent type 2 antigens,respectively,and marginal zone B-cell activation is impaired.Mechanistically,Zbtb24-deficient B cells show severe loss of DNA methylation in the promoter region of Il5ra(interleukin-5 receptor subunit alpha),and Il5ra derepression leads to elevated CD19 phosphorylation.Heterozygous disruption of Cd19 can revert the hypogammaglobulinemia phenotype of Zbtb24-deficient mice.Our results suggest the potential role of enhanced CD19 activity in immunodeficiency in ICF syndrome.展开更多
Dear Editor,Immunodeficiency,centromeric instability,and facial anomalies(ICF)syndrome is a rare autosomal recessive disorder characterized by antibody deficiency,facial dysmorphism,failure to thrive,and mental retard...Dear Editor,Immunodeficiency,centromeric instability,and facial anomalies(ICF)syndrome is a rare autosomal recessive disorder characterized by antibody deficiency,facial dysmorphism,failure to thrive,and mental retardation.Patients with ICF syndrome suffer from recurrent and often fatal infections in early childhood.A hallmark of ICF syndrome is loss of DNA methylation in special genomic regions,most notably satellite repeats at centromeric regions,which leads to heterochromatin decondensation and chromosomal abnormalities in lymphocytes(Ehrlich et al.,2008).展开更多
基金supported by grants from the Natural Science Foundation of Yunnan Province(Grant Nos.202001BC070001 and 202102AA100053)the National Natural Science Foundation of China(Grant No.32270845)+4 种基金Yunnan Fundamental Research Project(Grant No.202301AT070304)“Xingdian Talent Support Program”of Yunnan Province(Grant No.KKRD202273103)the Key Project of“Double First-Class”Initiative Joint Plan between Science and Technology of Yunnan and KUST(Grant No.202201BE070001-006)supported by grants from the US National Institutes of Health(Grant Nos.1R01AI12140301A1 and 1R01HD112473-01)Department of Defense(Grant No.ME220215).
文摘Cancer refers to a diverse collection of diseases characterized by several well-established hallmarks,including the abilities to sustain proliferative signaling,evade growth suppressors,activate invasion and metastasis,enable replicative immortality,induce angiogenesis,and resist cell death1.Historically,genetic alterations(deletions,point mutations,and translocations)were thought to be the basis for tumor formation via the inactivation of tumor suppressors and activation of oncogenes.
基金supported by the National Institutes of Health (CA179441, CA193124-Project 3 to Lei Li)
文摘DNA is constantly exposed to a wide array of genotoxic agents, generating a variety of forms of DNA damage. DNA-protein crosslinks(DPCs)—the covalent linkage of proteins with a DNA strand—are one of the most deleterious and understudied forms of DNA damage, posing as steric blockades to transcription and replication. If not properly repaired, these lesions can lead to mutations, genomic instability, and cell death. DPCs can be induced endogenously or through environmental carcinogens and chemotherapeutic agents. Endogenously, DPCs are commonly derived through reactions with aldehydes, as well as through trapping of various enzymatic intermediates onto the DNA. Proteolytic cleavage of the protein moiety of a DPC is a general strategy for removing the lesion. This can be accomplished through a DPC-specific protease and and/or proteasome-mediated degradation.Nucleotide excision repair and homologous recombination are each involved in repairing DPCs, with their respective roles likely dependent on the nature and size of the adduct. The Fanconi anemia pathway may also have a role in processing DPC repair intermediates. In this review, we discuss how these lesions are formed, strategies and mechanisms for their removal, and diseases associated with defective DPC repair.
文摘Dear Editor,Accumulating evidence suggests that dysregulated lysosomal membrane proteins,including vacuolar ATPase(v-ATPase)and the mammalian target of rapamycin(mTOR),are involved in tumorigenesis[1].Therefore,lysosomal proteins were proposed as potential therapeutic targets in cancer[1].As one of the lysosome-related signaling pathways,mTOR signaling regulates cell proliferation,survival,motility,and metabolism[2].SincemTOR signaling activation promotes tumorigenesis,mTOR inhibitors(mTORi),AZD8055[3],MLN0128[4],and Rapalink-1(the latest third-generation mTORi)[4],have been applied to several cancers.However,the limitations of mTORi include drug resistance and the lack of biomarkers.
基金supported by a grant(1R01AI12140301A1)from the National Institutes of Health(NIH)in the USA.
文摘Immunodeficiency,centromeric instability,and facial anomalies(ICF)syndrome is a rare autosomal recessive disorder characterized by DNA hypomethylation and antibody deficiency.It is caused by mutations in DNMT3B,ZBTB24,CDCA7,or HELLS.While progress has been made in elucidating the roles of these genes in regulating DNA methylation,little is known about the pathogenesis of the life-threatening hypogammaglobulinemia phenotype.Here,we show that mice deficient in Zbtb24 in the hematopoietic lineage recapitulate the major clinical features of patients with ICF syndrome.Specifically,Vav-Cre-mediated ablation of Zbtb24 does not affect lymphocyte development but results in reduced plasma cells and low levels of IgM,IgG1,and IgA.Zbtb24-deficient mice are hyper and hypo-responsive to T-dependent and T-independent type 2 antigens,respectively,and marginal zone B-cell activation is impaired.Mechanistically,Zbtb24-deficient B cells show severe loss of DNA methylation in the promoter region of Il5ra(interleukin-5 receptor subunit alpha),and Il5ra derepression leads to elevated CD19 phosphorylation.Heterozygous disruption of Cd19 can revert the hypogammaglobulinemia phenotype of Zbtb24-deficient mice.Our results suggest the potential role of enhanced CD19 activity in immunodeficiency in ICF syndrome.
基金This work was supported by grants(1R01AI1214030A1 to T.C.and CA16672 to the CCSG Cores at MDACC)from U.S.National Institutes of Health(NIH)and Core Facility Support Awards to MDACC(RP170628 to FCCIC and RP190507 to RAPC)from the Cancer Prevention and Research Institute of Texas(CPRIT).Z.Y.received a fellowship from the SamFreda Davis Fund.Y.Z.received a fellowship from the Thomas Endowment.N.V.was supported by a CPRIT Research Training Grant Award(RP170067)received a fellowship from the Center for Cancer Epigenetics(CCE)at MDACC and a scholarship from the Andrew Sowell-Wade Huggins Scholarship Fund.
文摘Dear Editor,Immunodeficiency,centromeric instability,and facial anomalies(ICF)syndrome is a rare autosomal recessive disorder characterized by antibody deficiency,facial dysmorphism,failure to thrive,and mental retardation.Patients with ICF syndrome suffer from recurrent and often fatal infections in early childhood.A hallmark of ICF syndrome is loss of DNA methylation in special genomic regions,most notably satellite repeats at centromeric regions,which leads to heterochromatin decondensation and chromosomal abnormalities in lymphocytes(Ehrlich et al.,2008).
