Meiosis is pivotal for sexual reproduction and fertility. Meiotic programmed DNA double-strand breaks(DSBs) initiate homologous recombination, ensuring faithful chromosome segregation and generation of gametes. Howeve...Meiosis is pivotal for sexual reproduction and fertility. Meiotic programmed DNA double-strand breaks(DSBs) initiate homologous recombination, ensuring faithful chromosome segregation and generation of gametes. However, few studies have focused on meiotic DSB formation in human reproduction.Here, we report four infertile siblings born to a consanguineous marriage, with three brothers suffering from non-obstructive azoospermia and one sister suffering from unexplained infertility with normal menstrual cycles and normal ovary sizes with follicular activity. An autosomal recessive mutation in TOP6BL was found co-segregating with infertility in this family. Investigation of one male patient revealed failure in programmed meiotic DSB formation and meiotic arrest prior to pachytene stage of prophase I.Mouse models carrying similar mutations to that in patients recapitulated the spermatogenic abnormalities of the patient. Pathogenicity of the mutation in the female patient was supported by observations in mice that meiotic programmed DSBs failed to form in mutant oocytes and oocyte maturation failure due to absence of meiotic recombination. Our study thus illustrates the phenotypical characteristics and the genotype-phenotype correlations of meiotic DSB formation failure in humans.展开更多
Plants are constantly exposed to microbial pathogens in the environment.One branch of innate plant immunity is mediated by cell-membrane-localized receptors,but less is known about associations between DNA damage and ...Plants are constantly exposed to microbial pathogens in the environment.One branch of innate plant immunity is mediated by cell-membrane-localized receptors,but less is known about associations between DNA damage and plant immune responses.Here,we show that rice(Oryza sativa)mesophyll cells are prone to DNA double-stranded breaks(DSBs)in response to ZJ173,a strain of Xanthomonas oryzae pv.oryzae(Xoo).The DSB signal transducer ataxia telangiectasia mutated(ATM),but not the ATM and Rad3-related branch,confers resistance against Xoo.Mechanistically,the MRE11–ATM module phosphorylates suppressor of gamma response 1(SOG1),which activates several phenylpropanoid pathway genes and prompts downstream phytoalexin biosynthesis during Xoo infection.Intriguingly,overexpression of the topoisomerase gene TOP6A3 causes a switch from the classic non-homologous end joining(NHEJ)pathway to the alternative NHEJ and homologous recombination pathways atXoo-induced DSBs.The enhanced ATM signaling of the alternative NHEJ pathway strengthens the SOG1-regulated phenylpropanoid pathway and thereby boosts Xoo-induced phytoalexin biosynthesis in TOP6A3-OE1 overexpression lines.Overall,the MRE11–ATM–SOG1 pathway serves as a prime example of plant–pathogen interactions that occur via host non-specific recognition.The function of TOP6-facilitated ATM signaling in the defense response makes it a promising target for breeding of rice germplasm that exhibits resistance to bacterial blight disease without a growth penalty.展开更多
基金supported by the National Key Research and Developmental Program of China (2018YFC1003700, 2016YFC1000600, 2018YFC1003400 and 2018YFC1004700)the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB19000000)the National Natural Science Foundation of China (31890780, 31630050, 31871514 and 31771668)。
文摘Meiosis is pivotal for sexual reproduction and fertility. Meiotic programmed DNA double-strand breaks(DSBs) initiate homologous recombination, ensuring faithful chromosome segregation and generation of gametes. However, few studies have focused on meiotic DSB formation in human reproduction.Here, we report four infertile siblings born to a consanguineous marriage, with three brothers suffering from non-obstructive azoospermia and one sister suffering from unexplained infertility with normal menstrual cycles and normal ovary sizes with follicular activity. An autosomal recessive mutation in TOP6BL was found co-segregating with infertility in this family. Investigation of one male patient revealed failure in programmed meiotic DSB formation and meiotic arrest prior to pachytene stage of prophase I.Mouse models carrying similar mutations to that in patients recapitulated the spermatogenic abnormalities of the patient. Pathogenicity of the mutation in the female patient was supported by observations in mice that meiotic programmed DSBs failed to form in mutant oocytes and oocyte maturation failure due to absence of meiotic recombination. Our study thus illustrates the phenotypical characteristics and the genotype-phenotype correlations of meiotic DSB formation failure in humans.
基金supported by the Guangzhou Science and Technology Planning Project (202201010790)the National Natural Science Foundation of China (32188102)+2 种基金the Guangdong Basic and Applied Basic Research Foundation (2023B1515020053)the Youth Innovation of Chinese Academy of Agricultural Sciences (Y20230C36)the specific research fund of The Innovation Platform for Academicians of Hainan Province (YSPTZX202303).
文摘Plants are constantly exposed to microbial pathogens in the environment.One branch of innate plant immunity is mediated by cell-membrane-localized receptors,but less is known about associations between DNA damage and plant immune responses.Here,we show that rice(Oryza sativa)mesophyll cells are prone to DNA double-stranded breaks(DSBs)in response to ZJ173,a strain of Xanthomonas oryzae pv.oryzae(Xoo).The DSB signal transducer ataxia telangiectasia mutated(ATM),but not the ATM and Rad3-related branch,confers resistance against Xoo.Mechanistically,the MRE11–ATM module phosphorylates suppressor of gamma response 1(SOG1),which activates several phenylpropanoid pathway genes and prompts downstream phytoalexin biosynthesis during Xoo infection.Intriguingly,overexpression of the topoisomerase gene TOP6A3 causes a switch from the classic non-homologous end joining(NHEJ)pathway to the alternative NHEJ and homologous recombination pathways atXoo-induced DSBs.The enhanced ATM signaling of the alternative NHEJ pathway strengthens the SOG1-regulated phenylpropanoid pathway and thereby boosts Xoo-induced phytoalexin biosynthesis in TOP6A3-OE1 overexpression lines.Overall,the MRE11–ATM–SOG1 pathway serves as a prime example of plant–pathogen interactions that occur via host non-specific recognition.The function of TOP6-facilitated ATM signaling in the defense response makes it a promising target for breeding of rice germplasm that exhibits resistance to bacterial blight disease without a growth penalty.
