
The BRCA1-BARD1 complex plays a dual role in DNA repair - it directly promotes long-range DNA end resection to initiate homologous recombination, while also protecting DNA from unscheduled degradation during replication stress, with the balance between these functions determined by the presence and concentration of the recombinase RAD51.


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BRCA1–BARD1 directly promotes double-strand break&nbsp;repair by stimulating long-range DNA end resection pathways.

Mechanism of BRCA1–BARD1 function in DNA end resection and DNA protection - Nature

mechanism-of-brca1-bard1-complex-in-regulating-dna-end-resection-and-protecting-dna-integrity


Mechanism of BRCA1-BARD1 Complex in Regulating DNA End Resection and Protecting DNA Integrity


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The human TIP60-C complex is a 20-subunit chromatin remodeling assembly that integrates histone exchange and acetylation activities, providing insights into the structural organization and recruitment mechanisms of this key regulator of chromatin dynamics.


Structure of human TIP60-C histone exchange and acetyltransferase complex - Nature

structure-and-functional-insights-into-the-human-tip60-c-chromatin-remodeling-complex


Structure and Functional Insights into the Human TIP60-C Chromatin Remodeling Complex



STAG3, a cohesin regulator traditionally associated with meiosis, plays a key role in post-transcriptional control of gene expression in the cytoplasm of mouse embryonic stem cells to facilitate their exit from the pluripotent state.


STAG proteins are key regulators of the cohesin complex and are often linked to alterations in cell identity and disease. Among the mammalian STAG paralogs, STAG3 has been less extensively studied beyond its known roles in meiosis. In this work, we demonstrate that STAG3 is expressed in mouse embryonic stem cells (mESCs) and primordial germ cell-like cells (PGCLCs), where it is required for cell fate decisions. Distinct from the other STAG proteins, STAG3 mediates its effects in the cytoplasm, facilitating the post-transcriptional regulation of gene expression. Furthermore, STAG3 localises to the centrosome independently of cohesin and interacts with proteins involved in mRNA localisation and stability. The knockdown of STAG3 in mESCs using siRNAs results in the destabilisation of the centrosome and the key P-body RNA-induced silencing complex (RISC) component TNRC6C, leading to the derepression of P-body localised mRNAs, such as DPPA3. Our results propose a model in which STAG3 collaborates with RNA-binding proteins (RBPs) and specific target mRNAs to control post-transcriptional gene expression and facilitate the transition from pluripotency in mESCs. Given that STAG3 is upregulated in various cancers, our results provide a novel perspective on how STAG proteins might contribute to cell identity and disease.

### Competing Interest Statement

The authors have declared no competing interest.

STAG3 promotes exit from pluripotency through post-transcriptional mRNA regulation in the cytoplasm

stag3-regulates-pluripotency-exit-and-cell-fate-decisions-through-post-transcriptional-mrna-control-in-the-cytoplasm


STAG3 Regulates Pluripotency Exit and Cell Fate Decisions through Post-transcriptional mRNA Control in the Cytoplasm



지카 바이러스는 IGF2BP2 리보핵단백질 복합체를 탈취하고 재구성하여 바이러스 복제 소기관 생성을 촉진한다.


Zika virus (ZIKV) infection causes significant human disease that, with no approved treatment or vaccine, constitutes a major public health concern. Its life cycle entirely relies on the cytoplasmic fate of the viral RNA genome (vRNA) through a fine-tuned equilibrium between vRNA translation, replication and packaging into new virions, all within virus-induced replication organelles (vRO). In this study, with an RNAi mini-screening and subsequent functional characterization, we have identified insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) as a new host dependency factor that regulates vRNA synthesis. In infected cells, IGF2BP2 associates with viral NS5 polymerase and redistributes to the perinuclear viral replication compartment. Combined fluorescence in situ hybridization-based confocal imaging, in vitro binding assays, and immunoprecipitation coupled to RT-qPCR, showed that IGF2BP2 directly interacts with ZIKV vRNA 3’-nontranslated region. Using ZIKV sub-genomic replicons and a replication-independent vRO induction system, we demonstrated that IGF2BP2 knockdown impairs de novo viral organelle biogenesis and, consistently, vRNA synthesis. Finally, the analysis of immunopurified IGF2BP2 complex using quantitative mass spectrometry and RT-qPCR, revealed that ZIKV infection alters the protein and RNA interactomes of IGF2BP2. Altogether, our data support that ZIKV hijacks and remodels the IGF2BP2 ribonucleoprotein complex to regulate vRO biogenesis and vRNA neosynthesis.

### Competing Interest Statement

The authors have declared no competing interest.

Zika virus remodels and hijacks IGF2BP2 ribonucleoprotein complex to promote viral replication organelle biogenesis

지카-바이러스가-igf2bp2-리보핵단백질-복합체를-재구성하고-탈취하여-바이러스-복제-소기관-생성을-촉진한다


지카 바이러스가 IGF2BP2 리보핵단백질 복합체를 재구성하고 탈취하여 바이러스 복제 소기관 생성을 촉진한다



Zika virus hijacks and remodels the host IGF2BP2 ribonucleoprotein complex to regulate viral replication organelle biogenesis and viral RNA synthesis.


zika-virus-hijacks-and-remodels-the-igf2bp2-ribonucleoprotein-complex-to-promote-viral-replication-organelle-biogenesis


Zika Virus Hijacks and Remodels the IGF2BP2 Ribonucleoprotein Complex to Promote Viral Replication Organelle Biogenesis



The balance of mTOR complexes (mTORC1 and mTORC2) in Sertoli cells regulates the rate of sperm epigenetic aging.


Over the past several decades, a trend toward delayed childbirth has led to increases in parental age at the time of conception. Sperm epigenome undergoes age-dependent changes increasing risks of adverse conditions in offspring conceived by fathers of advanced age. The mechanism(s) linking paternal age with epigenetic changes in sperm remain unknown. The sperm epigenome is shaped in a compartment protected by the blood-testes barrier (BTB) known to deteriorate with age. Permeability of the BTB is regulated by the balance of two mTOR complexes in Sertoli cells where mTOR complex 1 (mTORC1) promotes the opening of the BTB and mTOR complex 2 (mTORC2) promotes its integrity. We hypothesized that this balance is also responsible for age-dependent changes in the sperm epigenome. To test this hypothesis, we analyzed reproductive outcomes, including sperm DNA methylation in transgenic mice with Sertoli cell-specific suppression of mTORC1 (Raptor KO) or mTORC2 (Rictor KO). mTORC2 suppression accelerated aging of the sperm DNA methylome and resulted in a reproductive phenotype concordant with older age, including decreased testes weight and sperm counts, and increased percent of morphologically abnormal spermatozoa and mitochondrial DNA copy number. Suppression of mTORC1 resulted in the shift of DNA methylome in sperm opposite to the shift associated with physiological aging – sperm DNA methylome rejuvenation, and mild changes in sperm parameters. These results demonstrate for the first time that the balance of mTOR complexes in Sertoli cells regulates the rate of sperm epigenetic aging. Thus, mTOR pathway in Sertoli cells may be used as a novel target of therapeutic interventions to rejuvenate the sperm epigenome in advanced-age fathers.

Ethics statement All procedures followed the guidelines of the National Institutes of Health Guide for the Care and Use of Laboratory Animals and the approval for this study was received from the Institutional Animal Care and Use Committee at University of Massachusetts, Amherst.

### Competing Interest Statement

Alexander Suvorov is a CEO of ReGENE LLC. All other authors declare that they have no competing interests.

Mechanistic target of rapamycin (mTOR) pathway in Sertoli cells regulates age-dependent changes in sperm DNA methylation

mechanistic-target-of-rapamycin-mtor-pathway-in-sertoli-cells-regulates-age-dependent-changes-in-sperm-dna-methylation


Mechanistic Target of Rapamycin (mTOR) Pathway in Sertoli Cells Regulates Age-Dependent Changes in Sperm DNA Methylation



The cryo-EM structure of the CBC-ALYREF complex reveals that the RRM domain of ALYREF binds to both the NCBP1 and NCBP2 subunits of the CBC, providing molecular insights into how ALYREF recruits the mRNA export machinery to the 5' end of transcripts.


In eukaryotes, RNAs transcribed by RNA Pol II are modified at the 5’ end with a 7-methylguanosine (m7G) cap, which is recognized by the nuclear cap binding complex (CBC). The CBC plays multiple important roles in mRNA metabolism including transcription, splicing, polyadenylation, and export. It promotes mRNA export through direct interaction with a key mRNA export factor, ALYREF, which in turn links the TRanscription and EXport (TREX) complex to the 5’ end of mRNA. However, the molecular mechanism for CBC mediated recruitment of the mRNA export machinery is not well understood. Here, we present the first structure of the CBC in complex with an mRNA export factor, ALYREF. The cryo-EM structure of CBC-ALYREF reveals that the RRM domain of ALYREF makes direct contact with both the NCBP1 and NCBP2 subunits of the CBC. Comparing CBC-ALYREF with other cellular complexes containing CBC and/or ALYREF components provides insights into the coordinated events during mRNA transcription, splicing, and export.

### Competing Interest Statement

The authors have declared no competing interest.

Cryo-EM structure of the CBC-ALYREF complex

structural-insights-into-the-interaction-between-the-nuclear-cap-binding-complex-and-the-mrna-export-factor-alyref


Structural Insights into the Interaction between the Nuclear Cap Binding Complex and the mRNA Export Factor ALYREF



The nascent polypeptide-associated complex (NAC) orchestrates the sequential action of methionine aminopeptidase (MetAP) and N-acetyltransferase A (NatA) to mediate cotranslational N-terminal methionine excision and acetylation of nascent proteins.


Cotranslational N-terminal methionine excision and acetylation of eukaryotic proteins on ribosomes is coordinated by the nascent polypeptide-associated complex.

NAC guides a ribosomal multienzyme complex for nascent protein processing - Nature

nascent-polypeptide-associated-complex-coordinates-cotranslational-protein-processing-by-methionine-aminopeptidase-and-n-acetyltransferase


Nascent Polypeptide-Associated Complex Coordinates Cotranslational Protein Processing by Methionine Aminopeptidase and N-Acetyltransferase



The cryogenic electron microscopy structure of the Fcε–FcεRI complex reveals the molecular basis of FcεRI assembly and the asymmetric architecture of the FcRγ dimer, which is crucial for the signaling mechanisms of FcεRI and other immune receptors.


A study presents high-resolution cryogenic electron microscopy structures detailing how the elements of FcεRI assemble and how this receptor complex interacts with the target immunoglobulin E.

Structural insights into the high-affinity IgE receptor FcεRI complex - Nature

structural-insights-into-the-assembly-and-signaling-mechanisms-of-the-high-affinity-ige-receptor-fcεri-complex


Structural Insights into the Assembly and Signaling Mechanisms of the High-Affinity IgE Receptor FcεRI Complex



Topological stress and inhibition of RNA polymerase I can induce double-strand breaks in the ribosomal DNA locus, leading to the formation of PML-nucleolar compartments that segregate damaged rDNA from active nucleoli.


PML, a multifunctional protein, is crucial for forming PML-nuclear bodies involved in stress responses. Under specific conditions, PML associates with nucleolar caps formed after RNA polymerase I (RNAPI) inhibition, leading to PML-nucleolar associations (PNAs). This study investigates PNAs-inducing stimuli by exposing cells to various genotoxic stresses. We found that the most potent inducers of PNAs introduced topological stress and inhibited RNAPI. Doxorubicin, the most effective compound, induced double-strand breaks (DSBs) in the rDNA locus. PNAs co-localized with damaged rDNA, segregating it from active nucleoli. Cleaving the rDNA locus with I-PpoI confirmed rDNA damage as a genuine stimulus for PNAs. Inhibition of ATM, ATR kinases, and RAD51 reduced I-PpoI-induced PNAs, highlighting the importance of ATM/ATR-dependent nucleolar cap formation and homologous recombination (HR) in their triggering. I-PpoI-induced PNAs co-localized with rDNA DSBs positive for RPA32-pS33 but deficient in RAD51, indicating resected DNA unable to complete HR repair. Our findings suggest that PNAs form in response to persistent rDNA damage within the nucleolar cap, highlighting the interplay between PML/PNAs and rDNA alterations due to topological stress, RNAPI inhibition, and rDNA DSBs destined for HR. Cells with persistent PNAs undergo senescence, suggesting PNAs help avoid rDNA instability, with implications for tumorigenesis and aging.

### Competing Interest Statement

The authors have declared no competing interest.

Topological stress triggers persistent DNA lesions in ribosomal DNA with ensuing formation of PML-nucleolar compartment

topological-stress-induces-difficult-to-repair-dna-lesions-in-ribosomal-dna-leading-to-the-formation-of-pml-nucleolar-compartments


Topological Stress Induces Difficult-to-Repair DNA Lesions in Ribosomal DNA, Leading to the Formation of PML-Nucleolar Compartments
