Biology subjects

Sajid, A.

Publications and source records attributed to Sajid, A..

5 recordsLinked to original sources

bioRxiv2026

Aquarius RNA helicase Protects Pluripotent Stem Cell Identity

Pluripotent stem cells must reconcile rapid replication with a highly dynamic transcriptional program, creating an inherent susceptibility to transcription-replication conflicts (TRCs). We demonstrate that embryonic stem cells (ESCs) operate in a "resilient" replication mode, tolerating high genomic traffic through the constitutive upregulation of R-loop and TRC resolution pathways. Through a targeted functional screen, we identify the RNA helicase Aquarius (AQR) as an essential safeguard of this state. AQR depletion downregulates these resolution factors, collapsing this stress-resistant program and driving ESCs into unstable, heterogenous states, marked by increased transcriptional entropy and cell-to-cell noise. Mechanistically, we show that key identity-defining genes are preferentially located within R-loop and TRC prone regions, making them uniquely vulnerable to AQR depletion. Our findings establish AQR as a critical governor of transcriptional fidelity, demonstrating that genomic resilience is fundamental to maintaining pluripotent cell identity.

cell biology↗

bioRxiv2025

Replisome progression regulates R-loop mediated transcriptional repression

Maintaining cellular proliferation necessitates the synchronized activity of diverse molecular machineries operating in parallel on the genome. Wide-spread transcription and R-loop formation can interfere with genome duplication, causing transcription-replication conflicts (TRCs). Here, we use live-cell imaging for simultaneous monitoring of replication fork progression and transcription dynamics of an R-loop prone gene. While robust replisome progression through R-loops is observed in wild-type cells, it is impaired in RnaseH, Mph1 and Sen1 mutants. Intriguingly, we find that R-loop formation inhibits gene transcription, but this inhibition is reversed by replisome passage, demonstrating the dynamic crosstalk between replication, transcription and R-loops in a single cell cycle. Unexpectedly, we find that R-loops also have beneficial roles in reducing the density of RNAPII molecules on the gene, thereby preventing fork stalling upon high RNAPII occupancy. These findings illuminate that regulating R-loops and RNAPII density together is critical for preventing harmful TRCs.

cell biology↗

bioRxiv2023

Anopheles gambiae mosGILT regulates innate immune genes and zpg expression

Gene-edited mosquitoes lacking a gamma-interferon-inducible lysosomal thiol reductase-like protein, namely (mosGILTnull) have lower Plasmodium infection, which is linked to impaired ovarian development and immune activation. The transcriptome of mosGILTnull A. gambiae was therefore compared to wild type (WT) by RNA-sequencing to delineate mosGILT-dependent pathways. Compared to WT mosquitoes, mosGILTnull A. gambiae demonstrated altered expression of genes related to oogenesis, 20-hydroxyecdysone synthesis, as well as immune-related genes. Serendipitously, the zero population growth gene, zpg, an essential regulator of germ cell development was found to be one of the most downregulated genes in mosGILTnull mosquitoes. These results provide the crucial missing link between two previous studies on the role of zpg and mosGILT in ovarian development. This study further demonstrates that mosGILT has the potential to serve as a target for the biological control of mosquito vectors and to influence the Plasmodium life cycle within the vector.

genomics↗

bioRxiv2021

The Lyme Disease agent co-opts adiponectin receptor-mediated signaling in its arthropod vector

Adiponectin-mediated pathways contribute to mammalian homeostasis; however, little is known about adiponectin and adiponectin receptor signaling in arthropods. In this study, we demonstrate that Ixodes scapularis ticks have an adiponectin receptor-like protein (ISARL) but lack adiponectin - suggesting activation by alternative pathways. ISARL expression is significantly upregulated in the tick gut after Borrelia burgdorferi infection suggesting that ISARL-signaling may be co-opted by the Lyme disease agent. Consistent with this, RNA interference (RNAi)-mediated silencing of ISARL significantly reduced the B. burgdorferi burden in the tick. RNA-seq-based transcriptomics and RNAi assays demonstrate that ISARL-mediated phospholipid metabolism by phosphatidylserine synthase I is associated with B. burgdorferi survival. Furthermore, the tick complement C1q-like protein 3 interacts with ISARL, and B. burgdorferi facilitates this process. This study identifies a new tick metabolic pathway that is connected to the life cycle of the Lyme disease spirochete. Significance StatementAdiponectin binds to adiponectin receptors and participates in glucose and lipid metabolism in mammals. In this study, we found that ticks have an adiponectin receptor-like protein but lack adiponectin. Importantly, we demonstrated that the Lyme disease agent, Borrelia burgdorferi, takes advantage of the adiponectin receptor signaling pathway to establish infection in its arthropod vector, Ixodes scapularis. Our study sheds light on the understanding of Borrelia-tick interactions and provides insights into how a human infectious disease agent may evolve to manipulate host metabolism for its own benefits. Understanding this pathway may lead to new ways to interfere with the Borrelia life cycle, and this mechanism may be applicable to additional microbes that are transmitted by ticks, mosquitoes or other arthropods.

microbiology↗

bioRxiv2018

Structures of DPAGT1 explain glycosylation disease mechanisms and advance TB antibiotic design

Protein glycosylation is a widespread post-translational modification. The first committed step to the lipid-linked glycan used for this process is catalysed by dolichyl-phosphate N-acetylglucosamine-phosphotransferase DPAGT1 (GPT/E.C. 2.7.8.15). Missense DPAGT1 variants cause congenital myasthenic syndrome and congenital disorders of glycosylation. In addition, naturally-occurring bactericidal nucleoside analogues such as tunicamycin are toxic to eukaryotes due to DPAGT1 inhibition, preventing their clinical use as antibiotics. However, little is known about the mechanism or the effects of disease-associated mutations in this essential enzyme. Our structures of DPAGT1 with the substrate UDP-GlcNAc and tunicamycin reveal substrate binding modes, suggest a mechanism of catalysis, provide an understanding of how mutations modulate activity (and thus cause disease) and allow design of non-toxic lipid-altered tunicamycins. The structure-tuned activity of these analogues against several bacterial targets allowed design of potent antibiotics for Mycobacterium tuberculosis, enabling treatment in vitro, in cellulo and in vivo thereby providing a promising new class of antimicrobial drug.\n\nHighlightsO_LIStructures of DPAGT1 with UDP-GlcNAc and tunicamycin reveal mechanisms of catalysis\nC_LIO_LIDPAGT1 mutants in patients with glycosylation disorders modulate DPAGT1 activity\nC_LIO_LIStructures, kinetics and biosynthesis reveal role of lipid in tunicamycin\nC_LIO_LILipid-altered, tunicamycin analogues give non-toxic antibiotics against TB\nC_LI

biochemistry↗