The long-term effectiveness of targeted cancer therapies is limited by the development of resistance.Although epigenetic reprogramming has been implicated in resistance,the mechanisms remain elusive.Herein,we demonstr...The long-term effectiveness of targeted cancer therapies is limited by the development of resistance.Although epigenetic reprogramming has been implicated in resistance,the mechanisms remain elusive.Herein,we demonstrate that increased chromatin accessibility is involved in adaptive BRAF inhibitor(BRAFi)-resistance in melanoma cells.We observed loss of chromatin assembly factor 1(CAF-1)and its related histone H3 lysine 9 trimethylation(H3K9me3)with adaptive BRAFi resistance.We further showed that depletion of CAF-1 provides chromatin plasticity for effective reprogramming by AP1 components to promote BRAFi resistance.Our data sug-gest that therapeutic approaches to restore H3K9me3 levels may compensate for the loss of CAF-1 and,in turn,suppress resistance to BRAF inhibitors.展开更多
Chromatin is the primary carrier of epigenetic information in higher eukaryotes. AtCYP71 contains both cyclophilin domain and WD40 repeats. Loss of AtCYP71 function causes drastic pleiotropic phenotypic defects. Here,...Chromatin is the primary carrier of epigenetic information in higher eukaryotes. AtCYP71 contains both cyclophilin domain and WD40 repeats. Loss of AtCYP71 function causes drastic pleiotropic phenotypic defects. Here, we show that AtCYP71 physically interacts with FAS1 and LHP1, respectively, to modulate their distribution on chromatin. The Ihpl cyp71 double mutant showed more severe phenotypes than the single mutants, suggesting that AtCYP71 and LHP1 synergistically control plant development. Such synergism was in part illustrated by the observation that LHP1 association with its specific target loci requires AtCYP71 function. We also demonstrate that AtCYP71 physically interacts with FAS1 and is indispensable for FAS1 targeting to the KNAT1 locus. Together, our data suggest that AtCYP71 is involved in fundamental processes of chromatin assembly and histone modification in plants.展开更多
Ribonuclease P(RNase P)was first described in the 1970’s as an endoribonuclease acting in the maturation of precursor transfer RNAs(tRNAs).More recent studies,however,have uncovered non-canonical roles for RNase P an...Ribonuclease P(RNase P)was first described in the 1970’s as an endoribonuclease acting in the maturation of precursor transfer RNAs(tRNAs).More recent studies,however,have uncovered non-canonical roles for RNase P and its components.Here,we review the recent progress of its involvement in chromatin assembly,DNA damage response,and maintenance of genome stability with implications in tumorigenesis.The possibility of RNase P as a therapeutic target in cancer is also discussed.展开更多
基金supported by the National Institutes of Health to R.B.D.(NIH5P30CA015083)the Mayo Clinic Cancer Center Ea-gles Cancer Fund(Z.W.)the Mayo Clinic Center for Biomedical Discovery(S.M.O).
文摘The long-term effectiveness of targeted cancer therapies is limited by the development of resistance.Although epigenetic reprogramming has been implicated in resistance,the mechanisms remain elusive.Herein,we demonstrate that increased chromatin accessibility is involved in adaptive BRAF inhibitor(BRAFi)-resistance in melanoma cells.We observed loss of chromatin assembly factor 1(CAF-1)and its related histone H3 lysine 9 trimethylation(H3K9me3)with adaptive BRAFi resistance.We further showed that depletion of CAF-1 provides chromatin plasticity for effective reprogramming by AP1 components to promote BRAFi resistance.Our data sug-gest that therapeutic approaches to restore H3K9me3 levels may compensate for the loss of CAF-1 and,in turn,suppress resistance to BRAF inhibitors.
文摘Chromatin is the primary carrier of epigenetic information in higher eukaryotes. AtCYP71 contains both cyclophilin domain and WD40 repeats. Loss of AtCYP71 function causes drastic pleiotropic phenotypic defects. Here, we show that AtCYP71 physically interacts with FAS1 and LHP1, respectively, to modulate their distribution on chromatin. The Ihpl cyp71 double mutant showed more severe phenotypes than the single mutants, suggesting that AtCYP71 and LHP1 synergistically control plant development. Such synergism was in part illustrated by the observation that LHP1 association with its specific target loci requires AtCYP71 function. We also demonstrate that AtCYP71 physically interacts with FAS1 and is indispensable for FAS1 targeting to the KNAT1 locus. Together, our data suggest that AtCYP71 is involved in fundamental processes of chromatin assembly and histone modification in plants.
基金supported by the National Natural Science Foundation of China(Grant No.32090031)the Shenzhen Science and Technology Innovation Commission(Grant Nos.JCYJ20220818095616035 and JCYJ201805073000163).
文摘Ribonuclease P(RNase P)was first described in the 1970’s as an endoribonuclease acting in the maturation of precursor transfer RNAs(tRNAs).More recent studies,however,have uncovered non-canonical roles for RNase P and its components.Here,we review the recent progress of its involvement in chromatin assembly,DNA damage response,and maintenance of genome stability with implications in tumorigenesis.The possibility of RNase P as a therapeutic target in cancer is also discussed.
