The environmental presence of decabromodiphenyl ether(BDE-209),which is toxic to the male reproductive system,is widespread.The current study investigated its mechanism of toxicity in mice.The results showed,that BDE-...The environmental presence of decabromodiphenyl ether(BDE-209),which is toxic to the male reproductive system,is widespread.The current study investigated its mechanism of toxicity in mice.The results showed,that BDE-209 induced DNA damage,decreased the expression of the promoter of meiosis spermatogenesis-and oogenesis-specific basic helix-loop-helix 1(Sohlh1),meiosis related-factors Lethal(3)malignant brain tumor like 2(L3MBTL2),PIWI-like protein 2(MILI),Cyclin-dependent kinase 2(CDK2),Cyclin A,synaptonemal complex protein 1(SYCP1)and synaptonemal complex protein 3(SYCP3),and caused spermatogenic cell apoptosis,resulting in a decrease in sperm quantity and quality.Furthermore,BDE-209 downregulated the levels of anaphase-promoting complex/cyclosome(APC/C),increased the expression of PIWI-like protein 1(MIWI)in the cytoplasm of elongating spermatids,and decreased the nuclear levels of RING finger protein 8(RNF8),ubiquitinated(ub)-H2A/ub-H2B,and Protamine 1(PRM1)/Protamine 2(PRM2),while increasing H2A/H2B nuclear levels in spermatids.The reproductive toxicity was persistent for 50 days following the withdrawal of BDE-209 exposure.The results suggested that BDE-209 inhibits the initiation of meiosis by decreasing the expression of Sohlh1.Furthermore,the reduced expression of L3MBTL2 inhibited the formation of chromosomal synaptonemal complexes by depressing the expression of meiosis regulators affecting the meiotic progression and also inhibited histone ubiquitination preventing the replacement of histones by protamines,by preventing RNF8 from entering nuclei,which affected the evolution of spermatids into mature sperm.展开更多
大量遗传学研究表明,Piwi蛋白对于动物生殖系细胞发育具有至关重要的作用,Piwi基因敲除致动物不育。人Piwi(Hiwi)基因特异性地在雄性生殖细胞表达,但目前对其在人精子发生中的作用及其与男性不育的联系还知之甚少。该研究通过筛查临床...大量遗传学研究表明,Piwi蛋白对于动物生殖系细胞发育具有至关重要的作用,Piwi基因敲除致动物不育。人Piwi(Hiwi)基因特异性地在雄性生殖细胞表达,但目前对其在人精子发生中的作用及其与男性不育的联系还知之甚少。该研究通过筛查临床男性不育样本发现,少弱精症患者Hiwi基因中存在拮抗泛素化修饰的D-box元件突变;通过构建基因敲入小鼠模型证实,该突变导致雄性不育。机制研究表明,小鼠Piwi(Miwi)D-box突变致MIWI蛋白异常稳定存在于后期精子细胞中,导致与其相互作用的组蛋白泛素连接酶RNF8(ring finger protein 8)被扣留于细胞质、不能入核催化组蛋白泛素化修饰,进而抑制组蛋白被鱼精蛋白替换,引发精子形成异常、雄性不育。该研究发现了男性不育的一类新型致病基因突变,并发现了Piwi蛋白具有调控组蛋白泛素化修饰的新功能,揭示了精子形成中调控组蛋白–鱼精蛋白转换的重要机制。展开更多
DNA damage response(DDR) is essential for maintaining genome stability and protecting cells from tumorigenesis. Ubiquitin and ubiquitin-like modi?cations play an important role in DDR, from signaling DNA damage to med...DNA damage response(DDR) is essential for maintaining genome stability and protecting cells from tumorigenesis. Ubiquitin and ubiquitin-like modi?cations play an important role in DDR, from signaling DNA damage to mediating DNA repair. In this report, we found that the E3 ligase ring ?nger protein 126(RNF126) was recruited to UV laser micro-irradiation-induced stripes in a RNF8-dependent manner. RNF126 directly interacted with and ubiquitinated another E3 ligase, RNF168. Overexpression of wild type RNF126, but not catalytically-inactive mutant RNF126(CC229/232 AA), diminished ubiquitination of H2 A histone family member X(H2AX),and subsequent bleomycin-induced focus formation of total ubiquitin FK2, TP53-binding protein1(53 BP1), and receptor-associated protein 80(RAP80). Interestingly, both RNF126 overexpression and RNF126 downregulation compromised homologous recombination(HR)-mediated repair of DNA double-strand breaks(DSBs). Taken together, our ?ndings demonstrate that RNF126 negatively regulates RNF168 function in DDR and its appropriate cellular expression levels are essential for HR-mediated DSB repair.展开更多
Histone ubiquitylation has emerged as an important chromatin modification associated with DNA damage signaling and repair pathways.These histone marks,laid down by E3 ubiquitin ligases that include RNF8 and RNF168,dec...Histone ubiquitylation has emerged as an important chromatin modification associated with DNA damage signaling and repair pathways.These histone marks,laid down by E3 ubiquitin ligases that include RNF8 and RNF168,decorate chromatin domains surrounding DNA double-strand breaks(DSBs).Recent work implicated ubiquitylated histones in orchestrating cell cycle checkpoints,DNA repair and gene transcription.Here we summarize recent advances that contribute to our current knowledge of the highly dynamic nature of DSB-associated histone ubiquitylation,and discuss major challenges ahead in understanding the versatility of ubiquitin conjugation in maintaining genome stability.展开更多
基金supported by the National Natural Science Foundation of China(Nos.31971415 and 32171492)。
文摘The environmental presence of decabromodiphenyl ether(BDE-209),which is toxic to the male reproductive system,is widespread.The current study investigated its mechanism of toxicity in mice.The results showed,that BDE-209 induced DNA damage,decreased the expression of the promoter of meiosis spermatogenesis-and oogenesis-specific basic helix-loop-helix 1(Sohlh1),meiosis related-factors Lethal(3)malignant brain tumor like 2(L3MBTL2),PIWI-like protein 2(MILI),Cyclin-dependent kinase 2(CDK2),Cyclin A,synaptonemal complex protein 1(SYCP1)and synaptonemal complex protein 3(SYCP3),and caused spermatogenic cell apoptosis,resulting in a decrease in sperm quantity and quality.Furthermore,BDE-209 downregulated the levels of anaphase-promoting complex/cyclosome(APC/C),increased the expression of PIWI-like protein 1(MIWI)in the cytoplasm of elongating spermatids,and decreased the nuclear levels of RING finger protein 8(RNF8),ubiquitinated(ub)-H2A/ub-H2B,and Protamine 1(PRM1)/Protamine 2(PRM2),while increasing H2A/H2B nuclear levels in spermatids.The reproductive toxicity was persistent for 50 days following the withdrawal of BDE-209 exposure.The results suggested that BDE-209 inhibits the initiation of meiosis by decreasing the expression of Sohlh1.Furthermore,the reduced expression of L3MBTL2 inhibited the formation of chromosomal synaptonemal complexes by depressing the expression of meiosis regulators affecting the meiotic progression and also inhibited histone ubiquitination preventing the replacement of histones by protamines,by preventing RNF8 from entering nuclei,which affected the evolution of spermatids into mature sperm.
文摘大量遗传学研究表明,Piwi蛋白对于动物生殖系细胞发育具有至关重要的作用,Piwi基因敲除致动物不育。人Piwi(Hiwi)基因特异性地在雄性生殖细胞表达,但目前对其在人精子发生中的作用及其与男性不育的联系还知之甚少。该研究通过筛查临床男性不育样本发现,少弱精症患者Hiwi基因中存在拮抗泛素化修饰的D-box元件突变;通过构建基因敲入小鼠模型证实,该突变导致雄性不育。机制研究表明,小鼠Piwi(Miwi)D-box突变致MIWI蛋白异常稳定存在于后期精子细胞中,导致与其相互作用的组蛋白泛素连接酶RNF8(ring finger protein 8)被扣留于细胞质、不能入核催化组蛋白泛素化修饰,进而抑制组蛋白被鱼精蛋白替换,引发精子形成异常、雄性不育。该研究发现了男性不育的一类新型致病基因突变,并发现了Piwi蛋白具有调控组蛋白泛素化修饰的新功能,揭示了精子形成中调控组蛋白–鱼精蛋白转换的重要机制。
基金supported by the National Natural Science Foundation of China (Grant Nos.31530016 and 31761133012)the National Basic Research Program of China (Grant Nos.2015CB910601 and 2017YFA0503900)the Shenzhen Science and Technology Innovation Commission (Grant No.JCYJ20170412113009742 awarded to XX),China
文摘DNA damage response(DDR) is essential for maintaining genome stability and protecting cells from tumorigenesis. Ubiquitin and ubiquitin-like modi?cations play an important role in DDR, from signaling DNA damage to mediating DNA repair. In this report, we found that the E3 ligase ring ?nger protein 126(RNF126) was recruited to UV laser micro-irradiation-induced stripes in a RNF8-dependent manner. RNF126 directly interacted with and ubiquitinated another E3 ligase, RNF168. Overexpression of wild type RNF126, but not catalytically-inactive mutant RNF126(CC229/232 AA), diminished ubiquitination of H2 A histone family member X(H2AX),and subsequent bleomycin-induced focus formation of total ubiquitin FK2, TP53-binding protein1(53 BP1), and receptor-associated protein 80(RAP80). Interestingly, both RNF126 overexpression and RNF126 downregulation compromised homologous recombination(HR)-mediated repair of DNA double-strand breaks(DSBs). Taken together, our ?ndings demonstrate that RNF126 negatively regulates RNF168 function in DDR and its appropriate cellular expression levels are essential for HR-mediated DSB repair.
基金supported by Faculty Development Fund and Seed Funding for Applied Research to MSYH(No.201007160001).
文摘Histone ubiquitylation has emerged as an important chromatin modification associated with DNA damage signaling and repair pathways.These histone marks,laid down by E3 ubiquitin ligases that include RNF8 and RNF168,decorate chromatin domains surrounding DNA double-strand breaks(DSBs).Recent work implicated ubiquitylated histones in orchestrating cell cycle checkpoints,DNA repair and gene transcription.Here we summarize recent advances that contribute to our current knowledge of the highly dynamic nature of DSB-associated histone ubiquitylation,and discuss major challenges ahead in understanding the versatility of ubiquitin conjugation in maintaining genome stability.
