Preimplantation embryo arrest is a common cause of female infertility and recurrent failure of assisted reproductive technology.However,its genetic basis is largely unrevealed.Geminin,encoded by the GMNN gene,plays an...Preimplantation embryo arrest is a common cause of female infertility and recurrent failure of assisted reproductive technology.However,its genetic basis is largely unrevealed.Geminin,encoded by the GMNN gene,plays an important role in preventing DNA re-replication by inhibiting CDT1.Here,using whole-exome sequencing and Sanger sequencing,we identified three rare missense mutations of GMNN in females with preimplantation arrest,following a dominant inheritance pattern.The RNA sequencing data from both the mouse zygotes and the patient's one-cell embryo demonstrated the altered cell cycle processes.We then found that these mutations decreased the binding with CDT1 and resulted in activation of CHK1 and DNA damage,resulting in cell cycle disturbance.Our findings uncover a mechanistic understanding of the pathogenesis of human preimplantation embryo arrest,which acts by impairing the correct cell cycle and DNA rereplication procedure,and provides a new molecular target for the diagnosis and treatment of infertile patients.展开更多
DNA replication is a highly regulated process involving a number of licensing and replication factors that function in a carefully orchestrated manner to faithfully replicate DNA during every cell cycle.Loss of proper...DNA replication is a highly regulated process involving a number of licensing and replication factors that function in a carefully orchestrated manner to faithfully replicate DNA during every cell cycle.Loss of proper licensing control leads to deregulated DNA replication including DNA re-replication,which can cause genome instability and tumorigenesis.Eukaryotic organisms have established several conserved mechanisms to prevent DNA re-replication and to counteract its potentially harmful effects.These mechanisms include tightly controlled regulation of licensing factors and activation of cell cycle and DNA damage checkpoints.Deregulated licensing control and its associated compromised checkpoints have both been observed in tumor cells,indicating that proper functioning of these pathways is essential for maintaining genome stability.In this review,we discuss the regulatory mechanisms of licensing control,the deleterious consequences when both licensing and checkpoints are compromised,and present possible mechanisms to prevent re-replication in order to maintain genome stability.展开更多
基金supported by the National Natural Science Foundation of China(82192874,82402161,82071606,82171842,31988101)the National Key Research and Development Program of China(2024YFC3405600)+12 种基金Shandong Provincial Key Research and Development Program(2024CXPT087)Shandong Provincial Key Research and Development Program(2020ZLYS02)Taishan Scholars Program of Shandong Province(ts20190988)Ningxia Hui Autonomous Region Key Research and Developmental Program(2024BEG02019)China National Postdoctoral Program for Innovative Talent(BX20240172)China Postdoctoral Science Foundation(2024M751487)Youth Project of Jiangsu Provincial Natural Science Foundation(BK20240375)Postdoctoral Research Fund of Gusu School in Nanjing Medical University(GSBSHKY202303)Fundamental Research Funds of Shandong University(2023QNTDO04)the Science and Technology Innovation Program of Hunan Province(2023RC3233)the Scientific Research Foundation of Reproductive and Genetic Hospital of CITIC-XIANGYA(YNXM-202202)the Natural Science Foundation of Hunan Province(2024JJ2083)the Specific Research Fund of the Innovation Platform for Academicians of Hainan Province(YSPTZX202310)。
文摘Preimplantation embryo arrest is a common cause of female infertility and recurrent failure of assisted reproductive technology.However,its genetic basis is largely unrevealed.Geminin,encoded by the GMNN gene,plays an important role in preventing DNA re-replication by inhibiting CDT1.Here,using whole-exome sequencing and Sanger sequencing,we identified three rare missense mutations of GMNN in females with preimplantation arrest,following a dominant inheritance pattern.The RNA sequencing data from both the mouse zygotes and the patient's one-cell embryo demonstrated the altered cell cycle processes.We then found that these mutations decreased the binding with CDT1 and resulted in activation of CHK1 and DNA damage,resulting in cell cycle disturbance.Our findings uncover a mechanistic understanding of the pathogenesis of human preimplantation embryo arrest,which acts by impairing the correct cell cycle and DNA rereplication procedure,and provides a new molecular target for the diagnosis and treatment of infertile patients.
基金supported by the NIH R01 Grant CA102361 and NIH R01 Grant GM080677 to X.W.,and the NIH Training Grant DK007022-30 to L.T.
文摘DNA replication is a highly regulated process involving a number of licensing and replication factors that function in a carefully orchestrated manner to faithfully replicate DNA during every cell cycle.Loss of proper licensing control leads to deregulated DNA replication including DNA re-replication,which can cause genome instability and tumorigenesis.Eukaryotic organisms have established several conserved mechanisms to prevent DNA re-replication and to counteract its potentially harmful effects.These mechanisms include tightly controlled regulation of licensing factors and activation of cell cycle and DNA damage checkpoints.Deregulated licensing control and its associated compromised checkpoints have both been observed in tumor cells,indicating that proper functioning of these pathways is essential for maintaining genome stability.In this review,we discuss the regulatory mechanisms of licensing control,the deleterious consequences when both licensing and checkpoints are compromised,and present possible mechanisms to prevent re-replication in order to maintain genome stability.
