RESUMO
Although animals have evolved multiple mechanisms to suppress transposons, "leaky" mobilizations that cause mutations and diseases still occur. This suggests that transposons employ specific tactics to accomplish robust propagation. By directly tracking mobilization, we show that, during a short and specific time window of oogenesis, retrotransposons achieve massive amplification via a cell-type-specific targeting strategy. Retrotransposons rarely mobilize in undifferentiated germline stem cells. However, as oogenesis proceeds, they utilize supporting nurse cells-which are highly polyploid and eventually undergo apoptosis-as factories to massively manufacture invading products. Moreover, retrotransposons rarely integrate into nurse cells themselves but, instead, via microtubule-mediated transport, they preferentially target the DNA of the interconnected oocytes. Blocking microtubule-dependent intercellular transport from nurse cells significantly alleviates damage to the oocyte genome. Our data reveal that parasitic genomic elements can efficiently hijack a host developmental process to propagate robustly, thereby driving evolutionary change and causing disease.
Assuntos
Drosophila melanogaster/genética , Elementos Nucleotídeos Longos e Dispersos , Oogênese , RNA Interferente Pequeno , Retroelementos , Retroviridae/genética , Animais , Proteínas de Drosophila , Feminino , Biblioteca Gênica , Inativação Gênica , Células Germinativas , Proteínas de Fluorescência Verde/metabolismo , Hibridização in Situ Fluorescente , Masculino , Oócitos/metabolismo , Células-Tronco/metabolismoRESUMO
PIWI-interacting RNAs (piRNAs) silence transposons in germ cells to maintain genome stability and animal fertility. Rhino, a rapidly evolving heterochromatin protein 1 (HP1) family protein, binds Deadlock in a species-specific manner and so defines the piRNA-producing loci in the Drosophila genome. Here, we determine the crystal structures of Rhino-Deadlock complex in Drosophila melanogaster and simulans In both species, one Rhino binds the N-terminal helix-hairpin-helix motif of one Deadlock protein through a novel interface formed by the beta-sheet in the Rhino chromoshadow domain. Disrupting the interface leads to infertility and transposon hyperactivation in flies. Our structural and functional experiments indicate that electrostatic repulsion at the interaction interface causes cross-species incompatibility between the sibling species. By determining the molecular architecture of this piRNA-producing machinery, we discover a novel HP1-partner interacting mode that is crucial to piRNA biogenesis and transposon silencing. We thus explain the cross-species incompatibility of two sibling species at the molecular level.
Assuntos
Proteínas Cromossômicas não Histona/química , Proteínas de Drosophila/química , Proteínas Associadas aos Microtúbulos/química , Complexos Multiproteicos/química , RNA Interferente Pequeno/genética , Animais , Proteínas Cromossômicas não Histona/genética , Cristalografia por Raios X , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Genoma de Inseto/genética , Proteínas Associadas aos Microtúbulos/genética , Complexos Multiproteicos/genética , RNA Interferente Pequeno/química , Especificidade da EspécieRESUMO
Serving as a host factor for human immunodeficiency virus (HIV) integration, LEDGF/p75 has been under extensive study as a potential target for therapy. However, as a highly conserved protein, its physiological function remains to be thoroughly elucidated. Here, we characterize the molecular function of dP75, the Drosophila homolog of LEDGF/p75, during oogenesis. dP75 binds to transcriptionally active chromatin with its PWWP domain. The C-terminus integrase-binding domain-containing region of dP75 physically interacts with the histone kinase Jil-1 and stabilizes it in vivo. Together with Jil-1, dP75 prevents the spreading of the heterochromatin mark-H3K9me2-onto genes required for oogenesis and piRNA production. Without dP75, ectopical silencing of these genes disrupts oogenesis, activates transposons, and causes animal sterility. We propose that dP75, the homolog of an HIV host factor in Drosophila, partners with and stabilizes Jil-1 to ensure gene expression during oogenesis by preventing ectopic heterochromatin spreading.
Assuntos
Proteínas de Drosophila/genética , Infertilidade/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Oogênese/genética , Proteínas Serina-Treonina Quinases/genética , Animais , Linhagem Celular , Cromatina/genética , Drosophila/genética , HIV/genética , HIV/patogenicidade , Heterocromatina/genética , Humanos , Infertilidade/patologia , RNA Interferente Pequeno/genética , Integração Viral/genéticaRESUMO
The heavy occupancy of transposons in the genome implies that existing organisms have survived from multiple, independent rounds of transposon invasions. However, how and which host cell types survive the initial wave of transposon invasion remain unclear. We show that the germline stem cells can initiate a robust adaptive response that rapidly endogenizes invading P element transposons by activating the DNA damage checkpoint and piRNA production. We find that temperature modulates the P element activity in germline stem cells, establishing a powerful tool to trigger transposon hyper-activation. Facing vigorous invasion, Drosophila first shut down oogenesis and induce selective apoptosis. Interestingly, a robust adaptive response occurs in ovarian stem cells through activation of the DNA damage checkpoint. Within 4 days, the hosts amplify P element-silencing piRNAs, repair DNA damage, subdue the transposon, and reinitiate oogenesis. We propose that this robust adaptive response can bestow upon organisms the ability to survive recurrent transposon invasions throughout evolution.