Biology subjects

Zoch, A.

Publications and source records attributed to Zoch, A..

3 recordsLinked to original sources

bioRxiv2026

The structure of the apo-PIWI HSP90 complex

PIWI proteins are members of the Argonaute family and together with piRNAs protect metazoan germlines from transposons. PIWI proteins adopt a bi-lobed architecture with a central RNA-binding channel. HSP90 function has been linked to piRNA biogenesis, but the precise molecular mechanism is unresolved. Using the mammalian embryonic piRNA pathway as a model system, we find compelling evidence for the existence of PIWIL2- (MILI-) and PIWIL4- (MIWI2-) HSP90 complexes in foetal testis. We purify apo-PIWIL4-HSP90 from cells and determine its structure by cryo-electron microscopy. Distinct from piRNA-bound PIWI, apo-PIWIL4 adopts a unique and open conformation. The HSP90 dimer binds and unfolds PIWIs linker 1 domain. PIWIL4s N domain and the RNA-binding PAZ-MID-PIWI module are placed on opposite sides of the HSP90 dimers lumen. We further demonstrate that PIWI-HSP90 complexes, the open apo-PIWI conformation, and the HSP90 lumen-binding peptide are conserved features of PIWI proteins.

molecular biology↗

bioRxiv2024

PROSER1 Modulates DNA Demethylation through Dual Mechanisms to Prevent Syndromic Developmental Malformations

The link between DNA methylation and neurodevelopmental disorders is well established. However, how DNA methylation is fine-tuned - ensuring precise gene expression and developmental fidelity - remains poorly understood. PROSER1, a known TET2 interactor, was recently linked to a severe neurodevelopmental disorder. Here, we demonstrate that PROSER1 interacts with all TET enzymes and stabilizes chromatin-bound TET-OGT-PROSER1-DBHS (TOPD) complexes, which regulate DNA demethylation and developmental gene expression. Surprisingly, we find that PROSER1 also sequesters TET enzymes, preventing widespread demethylation and transposable element de-repression. Our findings identify PROSER1 as a key factor which both positively and negatively regulates DNA demethylation essential for mammalian neurodevelopment.

developmental biology↗

bioRxiv2024

MIWI arginines orchestrate generation of functional pachytene piRNAs and spermiogenesis

N-terminal arginine (NTR) methylation is a conserved feature of PIWI proteins, which are central components of the PIWI-interacting RNA (piRNA) pathway. The significance and precise function of PIWI NTR methylation in mammals remains unknown. In mice, PIWI NTRs bind Tudor domain containing proteins (TDRDs) that have essential roles in piRNA biogenesis and the formation of the chromatoid body. Using mouse MIWI (PIWIL1) as paradigm, we demonstrate that the NTRs are essential for spermatogenesis through the regulation of transposons and gene expression. Surprisingly, the loss of TDRD5 and TDRKH interaction with MIWI results in defective piRNA amplification, rather than an expected failure of piRNA biogenesis. We find that piRNA amplification is necessary for both transposon control and for sustaining levels of select, nonconserved, pachytene piRNAs that target specific mRNAs required for spermatogenesis. Our findings support the notion that the vast majority of pachytene piRNAs are dispensable, acting as autonomous genetic elements that rely for propagation on MIWI piRNA amplification. MIWI-NTRs also mediate interactions with TDRD6 that are necessary for chromatoid body compaction. Furthermore, MIWI-NTRs promote stabilization of spermiogenic transcripts that drive nuclear compaction, which is essential for sperm formation. In summary, the NTRs underpin the diversification of MIWI protein function. Key pointsO_LIMIWI-NTRs coordinate interactions with TDRDs required for piRNA biogenesis to sustain piRNA amplification C_LIO_LIMIWI-NTRs are necessary for both transposon control and for sustaining levels of select pachytene piRNAs that target specific mRNAs required for spermiogenesis C_LIO_LIMIWI-NTRs mediate interactions with TDRD6 to compact the Chromatoid Body C_LIO_LIMIWI-NTRs underlie stabilization of spermiogenic transcripts that drive nuclear compaction, which is essential for sperm formation C_LI

molecular biology↗