Biology subjects

ZHANG, S.

Publications and source records attributed to ZHANG, S..

5 recordsLinked to original sources

bioRxiv2026

MTERF1 loss buffers against pathogenic mtDNA deletions through transcriptional regulation

Large-scale mitochondrial DNA (mtDNA) deletions cripple oxidative phosphorylation once they exceed a critical heteroplasmy threshold, causing incurable mitochondrial pathologies. Using a genome-wide CRISPR/Cas9 screen in an engineered human cell line carrying a large-scale mtDNA deletion at high heteroplasmy, we identified mitochondrial transcription termination factor 1 (MTERF1) as a suppressor of the heteroplasmy burden. Loss of MTERF1 restored mitochondrial function and increased cellular proliferation in cells with a mtDNA deletion burden exceeding the pathogenic threshold, without altering heteroplasmy or mtDNA copy number. MTERF1 binds wild-type and deletion-bearing mitochondrial genomes indiscriminately at a site downstream of the ribosomal RNA genes and curbs transcription. Relieving this constraint broadly increased OXPHOS transcripts, thereby eliciting more respiratory output from the residual wild-type genomes. Notably, the buffering effect of MTERF1 loss extended beyond mtDNA deletions. In a counter-screen, MTERF1 loss could also restore respiratory growth in cells depleted of nuclear-encoded mitochondrial genes such as OPA1 and COX5A. Together, these findings indicate that by relieving a transcriptional constraint, MTERF1 loss compensates for reduced genome dosage, defining a strategy to enhance residual mitochondrial function in mtDNA deletion disorders and related conditions.

molecular biology↗

bioRxiv2025

Architecture and mechanism of a dual-enzyme retron system in prokaryotic immunity

Retrons are bacterial genetic retroelements encoding a reverse transcriptase (RT) and a non-coding RNA (ncRNA)-multi-copy single-stranded DNA (msDNA) hybrid. Diverse effector proteins or domains are found to associate with retrons, typically forming tripartite toxin-antitoxin systems involved in anti-phage defense. Although retrons have attracted growing interest in genome editing technologies, the mechanisms underlying most retron-mediated immune systems remain poorly understood. Here, we characterized a distinct quaternary retron system, Ec78, harboring a dual-enzymatic effector complex, in which the PtuA ATPase and PtuB nuclease act in concert to mediate phage clearance. The cryo-EM structure of the Ec78 complex adopts a flower-basket-like architecture, with two Ec78 retrons engaging the PtuAB effector complexes through a unique msDNA-insertion assembly mechanism. Interestingly, a sensing loop on the RT protein tightly monitors the length of the msDNA, which is likely responsible for phage detection and the subsequent release of the toxic effector complex. We further determined the cryo-EM structure of the retron-unbound effector complex, revealing an arginine-lysine finger loop on the PtuB nuclease that undergoes an ordered-to-disordered transition for enzymatic activation. Together, our work not only delineates the molecular basis underlying the Ec78 system in antiviral defense but also highlights the mechanistic diversity of retron systems in prokaryotic immunity.

biochemistry↗

bioRxiv2024

Continuous Prediction of Mice Lever-Pressing Kinematic Parameters by Background Removed Single-photon Calcium Images

Calcium imaging has gained extensive application in neural decoding tasks because of its high precision in observing cortical neural activity. Nevertheless, the immense data volume and complexity of automated signal extraction algorithms in calcium imaging result in significant delays in extracting neuronal calcium fluorescence signals, greatly constraining the efficiency of neural decoding research and its applicability in real-time tasks. Although a few studies have successfully used partial neuronal signals from calcium imaging data for real-time neural decoding and brain-computer interface tasks, they fail to leverage the complete neuronal dataset from experiments, which limits their ability to decode continuous and complex movements. In response to this challenge, we introduce a neural decoding method based on background-removed single-photon calcium images. This approach extracts three-dimensional spatiotemporal representations of neuronal activity via background removal and employs a decoder combining 3D-ResNet and RNN networks to enable continuous and rapid decoding of mouse lever-pressing kinematic parameters. Compared with traditional methods for neural decoding using single-photon calcium imaging, this approach offers higher accuracy and faster speed. Combined with real-time motion correction algorithms, the proposed neural decoding approach meets real-time decoding requirements at a 20Hz acquisition frame rate, achieving single decoding in just 21.8ms. This advancement significantly improves the efficiency of single-photon calcium imaging-based neural decoding, offering solutions for its application in real-time tasks, such as optical brain-computer interfaces.

neuroscience↗

bioRxiv2023

The G1/S transition is promoted by Rb degradation via the E3 ligase UBR5

Mammalian cells make the decision to divide at the G1/S transition in response to diverse signals impinging on the retinoblastoma protein Rb, a cell cycle inhibitor and tumor suppressor. Rb is inhibited by two parallel pathways. In the canonical pathway, Cyclin D-Cdk4/6 kinase complexes phosphorylate and inactivate Rb. In the second, recently discovered pathway, Rbs concentration decreases during G1 to promote cells progressing through the G1/S transition. However, the mechanisms underlying this second pathway are unknown. Here, we found that Rbs concentration drop in G1 and recovery in S/G2 is controlled by phosphorylation-dependent protein degradation. In early G1 phase, un- and hypo-phosphorylated Rb is targeted by the E3 ligase UBR5. UBR5 knockout cells have higher Rb concentrations in early G1, exhibit a lower G1/S transition rate, and are more sensitive to Cdk4/6 inhibition. This last observation suggests that UBR5 inhibition can strengthen the efficacy of Cdk4/6 inhibitor-based cancer therapies.

cell biology↗

bioRxiv2017

Activity of Sulfa Drugs and Their Combinations against Stationary Phase B. burgdorferi in vitro

Lyme disease is a most common vector borne disease in the US. Although the majority of Lyme patients can be cured with the standard 2-4 week antibiotic treatment, at least 10-20% of patients continue to suffer from prolonged post-treatment Lyme disease syndrome (PTLDS). While the cause for this is unclear, one possibility is that persisting organisms are not killed by current Lyme antibiotics. In our previous studies, we screened an FDA drug library and an NCI compound library on B. burgdorferi and found some drug hits including sulfa drugs as having good activity against B. burgdorferi stationary phase cells. In this study, we evaluated the relative activity of three commonly used sulfa drugs sulfamethoxazole (Smx), dapsone (Dps), sulfachlorpyridazine (Scp), and also trimethoprim (Tmp), and assessed their combinations with the commonly prescribed Lyme antibiotics for activities against B. burgdorferi stationary phase cells. Using the same molarity concentration, dapsone, sulfachlorpyridazine and trimethoprim showed very similar activity against stationary phase B. burgdorferi enriched in persisters, however, sulfamethoxazole was the least active drug among the three sulfa drugs tested. Interestingly, contrary to other bacterial systems, Tmp did not show synergy in drug combinations with the three sulfa drugs at their clinically relevant serum concentrations against B. burgdorferi. We found that sulfa drugs combined with other antibiotics were more active than their respective single drugs and that four-drug combinations were more active than three-drug combinations. Four drug combinations dapsone+minocycline+cefuroxime+azithromycin and dapsone+minocycline+cefuroxime+rifampin showed best activity against stationary phase B. burgdorferi in these sulfa drug combinations. However, these 4-sulfa drug containing combinations still had considerably less activity against B. burgdorferi stationary phase cells than the daptomycin+cefuroxime+doxycycline used as a positive control which completely eradicated B. burgdorferi stationary phase cells. Future studies are needed to evaluate and optimize the sulfa drug combinations in vitro and also in animal models.

microbiology↗