Scientists from the Cold Spring Harbor Laboratory have made important progress in understanding the earliest steps in the process of protecting animal genomes from potentially dangerous genetic elements called transposons. If they are out of control, these genomic parasites may spread indiscriminately, leading to infertility.
Professor Gregory J. Hannon and Leemor Joshua-Tor at the Cold Spring Harbor Laboratory jointly led the study. Professor Hannon is a pioneer in the field of small RNA research. He once edited the technical manual of Cold Spring Harbor Laboratory: "MicroRNA Research Methods" and so on. Structural biologist Joshua-Tor has achieved great results in the field of structural biology. She was selected as an HHMI researcher in the same year as Professor Shi Yigong of Tsinghua University.
In this article, Hannon and Joshua-Tor teamed up to explore this process in detail with the help of a genome guard called Piwi-interacting RNA (piRNA) generated in germ cells.
piRNAs are 26-31 nucleotides in length and bind to a class of small RNA molecules called reproductive specific proteins called PIWIs. Together, the two form a molecular silencing machine called RISC (RNA Induced Silencing Complex), which targets genomic parasites with extremely high efficiency. RISC prevents the activation of parasitic sequences, thereby preventing their subsequent amplification and reinsertion into the germ cell genome. If piRNA control is lost or destroyed, active mobile elements will be randomly inserted into the germ cell genome causing mutations, severe chromosomal abnormalities, and eventually infertility.
However, scientists are still not very clear about the biosynthesis of piRNA, the way these specific molecular silencers are generated. In the experiment, Astrid D. Haase, a postdoctoral researcher in Hannon's laboratory, and Jonathan J. Ipsaro in Joshua-Tor's laboratory, studied the Zucchini protein that was previously found to be involved in piRNAs biosynthesis. Its purpose is to explain its exact role in the biosynthesis process.
In previous studies of Drosophila, Haase, Hannon and others confirmed that when Zucchini is not expressed, single-stranded RNAs that are precursors of functional piRNAs will accumulate in the germ cells. This indicates that Zucchini is a necessary condition for piRNA biosynthesis, but the molecular basis of this mechanism is not yet clear.
Haase explained: "From our research work we know the function of Zucchini in the initial processing step, in this step the long piRNA precursor molecule is cleaved into shorter fragments. If it works normally, this cleavage is at least There is a need for an endonuclease (an enzyme with very specific characteristics).
The team knows that Zucchini (its analog in mice is called mouse Zucchini, formerly known as PLD6 / MitoPLD) belongs to a family of enzymes called phosphodiesterases. This family includes many members, either acting as phospholipases, cleaving phospholipid molecules, or as nucleases, cleaving nucleic acid strands. Some people doubt it, but they are not sure. Like Drosophila, Zucchini protein is a nuclease that can specifically cleave the connection between nucleic acid (DNA and RNA) nucleotide subunits.
In the latest Nature article, the research team reported the results of biochemical analysis confirming that mZuc does not have phospholipase activity, it actually has nuclease activity.
Ipsaro and Joshua-Tor conducted a complex structure analysis to support this finding and elucidate the molecular basis of mZuc action. Through X-ray crystallography, the researchers found that the shape of the mZuc protein binding site is consistent with its nuclease identity. Structural comparison of different members of various phosphodiesterase families supports this finding.
"Based on this data, we propose that the Zucchini protein is actually a nuclease whose function is to process the primary piRNA transcript into shorter fragments. This is the first critical step in the functional piRNA biosynthesis," Ipsaro And Haase reported.
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