CtBP-interacting protein(CtIP)is known for its multifaceted roles in DNA repair and genomic stability,directing the homologous recombination-mediated DNA double-stranded break repair pathway via DNA end resection,an e...CtBP-interacting protein(CtIP)is known for its multifaceted roles in DNA repair and genomic stability,directing the homologous recombination-mediated DNA double-stranded break repair pathway via DNA end resection,an essential error-free repair process vital for genome stability.Mammalian oocytes are highly prone to DNA damage accumulation due to prolonged G2/prophase arrest.Here,we explore the functions of CtIP in meiotic cell cycle regulation via a mouse oocyte model.Depletion of CtIP by siRNA injection results in delayed germinal vesicle breakdown and failed polar body extrusion.Mechanistically,CtIP deficiency increases DNA damage and decreases the expression and nuclear entry of CCNB1,resulting in marked impairment of meiotic resumption,which can be rescued by exogenous CCNB1 overexpression.Furthermore,depletion of CtIP disrupts microtubule-organizing centers coalescence at spindle poles as indicated by failed accumulation ofγ-tubulin,p-Aurora kinase A,Kif2A,and TPX2,leading to abnormal spindle assembly and prometaphase arrest.These results provide valuable insights into the important roles of CtIP in the G2/M checkpoint and spindle assembly in mouse oocyte meiotic cell cycle regulation.展开更多
The expression of retinoblastoma and several retinoblastoma-related genes was studied in glioma cell line U87 and its subline with knockdown of ERN1 (endoplasmic reticulum—nuclei-1), the main endoplasmic reticulum st...The expression of retinoblastoma and several retinoblastoma-related genes was studied in glioma cell line U87 and its subline with knockdown of ERN1 (endoplasmic reticulum—nuclei-1), the main endoplasmic reticulum stress sensing and signaling enzyme. It was shown that a blockade of the ERN1 enzyme function increases the expression levels of retinoblastoma, retinoblastoma-like 1 and most retinoblastoma related genes: EID1, JARID1B, E2F1, E2F3, RBAP48 and CTIP, does not change RNF40 and RBAP46 and decreases KDM5A. We have also demonstrated that hypoxia reduces the expression levels of retinoblastoma, EID1, and E2F1 in ERN1-deficient glioma cells only. At the same time, the expression levels of retinoblastoma-like 1, E2F3, RBAP46, RBAP48 and CTIP decrease, while JARID1B and RBBP2 increase in both types of cells in hypoxic conditions, but the expression is much stronger in cells with suppressed function of ERN1. The expression level of JARID1B and KDM-5A mRNA is also enhanced in glutamine deprivation condition in both tested cell types, moreover, this effect is amplified by the blockade of the ERN1 enzyme function. The expression levels of retinoblastoma, EID1, RBAP48, and E2F3 are decreased in glutamine deprivation condition only in ERN1-deficient glioma cells, but RBL1, CTIP, RBAP46, and E2F1—in both tested cell types with more significant effect in ERN1-deficient cells. Glucose deprivation condition leads to a decrease of expression levels of retinoblastoma, RBL1, E2F3, RBAP46, and RBAP48 in both used cell types and of EID1 and E2F1 only in glioma cells with suppressed function of signaling enzyme ERN1. Thus, expression levels of retinoblastoma and most retinoblastoma-related genes are increased under a blockade of ERN1 enzyme function and significantly changed in hypoxia, glucose or glutamine deprivation conditions both in control U87 cells and ERN1-deficient cells, but inhibition of the unfolded protein response sensor ERN1 predominantly enhances these effects. Moreover, it is possible that the induction of the expression of retinoblastoma and most retinoblastoma-related genes after knockdown of ERN1 plays an important role in suppression of glioma proliferation.展开更多
DNA double-strand break(DSB) is the most severe form of DNA damage,which is repaired mainly through high-fidelity homologous recombination(HR) or error-prone non-homologous end joining(NHEJ).Defects in the DNA damage ...DNA double-strand break(DSB) is the most severe form of DNA damage,which is repaired mainly through high-fidelity homologous recombination(HR) or error-prone non-homologous end joining(NHEJ).Defects in the DNA damage response lead to genomic instability and ultimately predispose organs to cancer.Nicotinamide phosphoribosyltransferase(Nampt),which is involved in nicotinamide adenine dinucleotide metabolism,is overexpressed in a variety of tumors.In this report,we found that Nampt physically associated with CtIP and DNA-PKcs/Ku80,which are key factors in HR and NHEJ,respectively.Depletion of Nampt by small interfering RNA(siRNA) led to defective NHEJ-mediated DSB repair and enhanced HR-mediated repair.Furthermore,the inhibition of Nampt expression promoted proliferation of cancer cells and normal human fibroblasts and decreased β-galactosidase staining,indicating a delay in the onset of cellular senescence in normal human fibroblasts.Taken together,our results suggest that Nampt is a suppressor of HR-mediated DSB repair and an enhancer of NHEJ-mediated DSB repair,contributing to the acceleration of cellular senescence.展开更多
The zinc finger transcription factor B-cell CLL/lymphoma 11B gene(BCL11B,CTIP2)plays a crucial role in T-cell development,but its role in T-cell malignancies has not yet been definitively clarified.In the literature,2...The zinc finger transcription factor B-cell CLL/lymphoma 11B gene(BCL11B,CTIP2)plays a crucial role in T-cell development,but its role in T-cell malignancies has not yet been definitively clarified.In the literature,2 contradictory hypotheses on the function of BCL11B exist.One suggests that BCL11B functions as tumor suppressor gene,and the other suggests that BCL11B functions as oncogene.The aim of this review is to revise the current knowledge about the function of BCL11B in T-cell malignancies,confront these 2 hypotheses and present a new model of dual role of BCL11B in T-cell malignancies and potential new therapeutic approach,based on recent findings of the function of BCL11B in DNA damage repair.Decreased BCL11B expression,resulting in deficient DNA repair,may facilitate DNA mutations in rapidly proliferating T-cell progenitors that undergo gene rearrangements,thereby leading to malignant transformation.On the other hand,decreased BCL11B expression and inefficient DNA repair may result in accumulation of DNA damages in genes crucial for the cell survival and in apoptosis of malignant T cells.We hypothesize that T-cell malignancies expressing high levels of BCL11B might be dependent on it.In those cases,targeted inhibition of BCL11B expression may have a therapeutic effect.The antitumor effect of BCL11B suppression might be strengthened by generation of induced T to NK cells(ITNK).Therefore,there is an urgent need to develop a specific BCL11B inhibitor.展开更多
基金supported by National Natural Science Foundation of China(32570854)Science and Technology Program of Guangzhou,China(2023A03J0258)Guangdong Basic and Applied Basic Research Foundation,China(2023B1515120027)。
文摘CtBP-interacting protein(CtIP)is known for its multifaceted roles in DNA repair and genomic stability,directing the homologous recombination-mediated DNA double-stranded break repair pathway via DNA end resection,an essential error-free repair process vital for genome stability.Mammalian oocytes are highly prone to DNA damage accumulation due to prolonged G2/prophase arrest.Here,we explore the functions of CtIP in meiotic cell cycle regulation via a mouse oocyte model.Depletion of CtIP by siRNA injection results in delayed germinal vesicle breakdown and failed polar body extrusion.Mechanistically,CtIP deficiency increases DNA damage and decreases the expression and nuclear entry of CCNB1,resulting in marked impairment of meiotic resumption,which can be rescued by exogenous CCNB1 overexpression.Furthermore,depletion of CtIP disrupts microtubule-organizing centers coalescence at spindle poles as indicated by failed accumulation ofγ-tubulin,p-Aurora kinase A,Kif2A,and TPX2,leading to abnormal spindle assembly and prometaphase arrest.These results provide valuable insights into the important roles of CtIP in the G2/M checkpoint and spindle assembly in mouse oocyte meiotic cell cycle regulation.
文摘The expression of retinoblastoma and several retinoblastoma-related genes was studied in glioma cell line U87 and its subline with knockdown of ERN1 (endoplasmic reticulum—nuclei-1), the main endoplasmic reticulum stress sensing and signaling enzyme. It was shown that a blockade of the ERN1 enzyme function increases the expression levels of retinoblastoma, retinoblastoma-like 1 and most retinoblastoma related genes: EID1, JARID1B, E2F1, E2F3, RBAP48 and CTIP, does not change RNF40 and RBAP46 and decreases KDM5A. We have also demonstrated that hypoxia reduces the expression levels of retinoblastoma, EID1, and E2F1 in ERN1-deficient glioma cells only. At the same time, the expression levels of retinoblastoma-like 1, E2F3, RBAP46, RBAP48 and CTIP decrease, while JARID1B and RBBP2 increase in both types of cells in hypoxic conditions, but the expression is much stronger in cells with suppressed function of ERN1. The expression level of JARID1B and KDM-5A mRNA is also enhanced in glutamine deprivation condition in both tested cell types, moreover, this effect is amplified by the blockade of the ERN1 enzyme function. The expression levels of retinoblastoma, EID1, RBAP48, and E2F3 are decreased in glutamine deprivation condition only in ERN1-deficient glioma cells, but RBL1, CTIP, RBAP46, and E2F1—in both tested cell types with more significant effect in ERN1-deficient cells. Glucose deprivation condition leads to a decrease of expression levels of retinoblastoma, RBL1, E2F3, RBAP46, and RBAP48 in both used cell types and of EID1 and E2F1 only in glioma cells with suppressed function of signaling enzyme ERN1. Thus, expression levels of retinoblastoma and most retinoblastoma-related genes are increased under a blockade of ERN1 enzyme function and significantly changed in hypoxia, glucose or glutamine deprivation conditions both in control U87 cells and ERN1-deficient cells, but inhibition of the unfolded protein response sensor ERN1 predominantly enhances these effects. Moreover, it is possible that the induction of the expression of retinoblastoma and most retinoblastoma-related genes after knockdown of ERN1 plays an important role in suppression of glioma proliferation.
基金was supported by the National Natural Science Foundation of China (No.31130017, 31071190, and 30711120570)the 973 project 2010CB911904+1 种基金Funding Project for Academic Human Resources Development in Institutions of Higher Learning Under the Jurisdiction of Beijing Municipality (No. PHR20110508) to XXthe 973 project 2012CB911203 to YSC
文摘DNA double-strand break(DSB) is the most severe form of DNA damage,which is repaired mainly through high-fidelity homologous recombination(HR) or error-prone non-homologous end joining(NHEJ).Defects in the DNA damage response lead to genomic instability and ultimately predispose organs to cancer.Nicotinamide phosphoribosyltransferase(Nampt),which is involved in nicotinamide adenine dinucleotide metabolism,is overexpressed in a variety of tumors.In this report,we found that Nampt physically associated with CtIP and DNA-PKcs/Ku80,which are key factors in HR and NHEJ,respectively.Depletion of Nampt by small interfering RNA(siRNA) led to defective NHEJ-mediated DSB repair and enhanced HR-mediated repair.Furthermore,the inhibition of Nampt expression promoted proliferation of cancer cells and normal human fibroblasts and decreased β-galactosidase staining,indicating a delay in the onset of cellular senescence in normal human fibroblasts.Taken together,our results suggest that Nampt is a suppressor of HR-mediated DSB repair and an enhancer of NHEJ-mediated DSB repair,contributing to the acceleration of cellular senescence.
基金supported in part by the National Centre for Research and Development,Poland(No.WPC/BCL/2019)the Intergovernmental International Cooperation on Scientific and Technological Innovation Project of Chinese Ministry of Science and Technology(No.2017YFE0131600).
文摘The zinc finger transcription factor B-cell CLL/lymphoma 11B gene(BCL11B,CTIP2)plays a crucial role in T-cell development,but its role in T-cell malignancies has not yet been definitively clarified.In the literature,2 contradictory hypotheses on the function of BCL11B exist.One suggests that BCL11B functions as tumor suppressor gene,and the other suggests that BCL11B functions as oncogene.The aim of this review is to revise the current knowledge about the function of BCL11B in T-cell malignancies,confront these 2 hypotheses and present a new model of dual role of BCL11B in T-cell malignancies and potential new therapeutic approach,based on recent findings of the function of BCL11B in DNA damage repair.Decreased BCL11B expression,resulting in deficient DNA repair,may facilitate DNA mutations in rapidly proliferating T-cell progenitors that undergo gene rearrangements,thereby leading to malignant transformation.On the other hand,decreased BCL11B expression and inefficient DNA repair may result in accumulation of DNA damages in genes crucial for the cell survival and in apoptosis of malignant T cells.We hypothesize that T-cell malignancies expressing high levels of BCL11B might be dependent on it.In those cases,targeted inhibition of BCL11B expression may have a therapeutic effect.The antitumor effect of BCL11B suppression might be strengthened by generation of induced T to NK cells(ITNK).Therefore,there is an urgent need to develop a specific BCL11B inhibitor.
