Biology subjects

Ganguly, P.

Publications and source records attributed to Ganguly, P..

8 recordsLinked to original sources

bioRxiv2026

Targeting TMPRSS2-ERG Fusion-Driven Prostate Cancer using Novel HBS-α-Helicomimics

Gene fusions between the androgen receptor (AR)-responsive gene TMPRSS2 and ERG occur in approximately 50% of prostate cancers (PCa), thereby promoting tumorigenesis through aberrant ERG expression. Therapeutic targeting of transcription factor-DNA interfaces remains a formidable challenge, largely owing to the entropic penalty associated with peptide folding during target engagement. Here, we describe the structure-guided design and preclinical evaluation of hydrogen-bond surrogate (HBS)-constrained alpha-helicomimics targeting the ERG-DNA recognition interface. Structural analysis of ERG-DNA complex revealed that DNA binding induces elongation of recognition helix H4 from approximately 2.5 to 4.0 helical turns. To stabilize the bioactive conformation, we incorporated an N-terminal HBS macrocycle, introduced D363E and S366E mutations to enhance DNA binding and structural stability, and added dual NLS-TAT tags to facilitate cellular delivery. Biochemical and cellular assays demonstrated that the lead compound, ERG helicomimics, competitively inhibited ERG binding to ETS motifs, disrupted ERG association with AR and other cofactors, leading to suppressed ERG transcriptional activity. Chromatin immunoprecipitation-qPCR confirmed reduced ERG occupancy at regulatory regions of canonical target genes, accompanied by downregulation of ERG-driven transcriptional programs. ERG helicomimics also reduced proliferation, migration, and invasion in ERG-positive PCa cells. In a murine xenograft model of TMPRSS2-ERG-positive PCa, systemic ERG helicomimics treatment suppressed tumor growth without overt toxicity and reduced Ki-67 expression compared with the designated control peptide. Collectively, our findings support HBS-constrained ERG helicomimics as a rational strategy for targeting ERG-driven PCa and warrant further therapeutic optimization.

cancer biology↗

bioRxiv2025

U.S. Visa Bureaucracy and Its Burdens Among Early Career Scholars

Foreign-born research scholars on temporary visas are essential to the U.S. scientific workforce and economy, yet they face systemic challenges shaped by restrictive immigration policies. While scholars across disciplines have long analyzed the evolution of U.S. immigration regimes and citizenship privilege, there remains a critical lack of quantitative data on the financial, temporal, and psychological burdens associated with visa bureaucracy. Here we present original survey data from more than 700 international postdoctoral researchers at Harvard Medical School (HMS) and its affiliated institutions, revealing how visa-related burdens directly impact scholars and their research. For example, over 40% of scholars reported spending more than a month in their home countries to renew U.S. visas, with 5% spending more than six months. Scholars from Asia experienced longer delays and higher costs than those from Europe. Seventy-five percent of respondents reported mental health challenges related to visa stress, often feeling trapped at work, with some requiring medication and time off. Our findings underscore the urgent need for targeted institutional support to promote research productivity, equitable opportunity, and mental well-being. As the U.S. repositions itself as a global scientific leader, such reforms will be critical to recruiting and retaining top talent and advancing equity in science.

scientific communication and education↗

bioRxiv2023

Tau P301L mutation promotes core 4R tauopathy fibril fold through near-surface water structuring and conformational rearrangement

Tau forms toxic fibrillar aggregates in a family of neurodegenerative diseases known as tauopathies. The faithful replication of tauopathy-specific fibril structures is a critical gap for developing diagnostic and therapeutic tools. This study debuts a strategy of identifying a critical segment of tau that forms a folding motif that is characteristic of a family of tauopathies and isolating it as a standalone peptide that form seeding-competent fibrils. The 19-residue jR2R3 peptide (295-313) spanning the R2/R3 splice junction of tau, in the presence of P301L, forms seeding-competent amyloid fibrils. This tau fragment contains the hydrophobic VQIVYK hexapeptide that is part of the core of every pathological tau fibril structure solved to-date and an intramolecular counter-strand that stabilizes the strand-loop-strand (SLS) motif observed in 4R tauopathy fibrils. This study shows that P301L exhibits a duality of effects: it lowers the barrier for the peptide to adopt aggregation-prone conformations and enhances the local structuring of water around the mutation site that facilitates site-specific dewetting and in-register stacking of tau to form cross {beta}-sheets. We solve a 3 [A] cryo-EM structure of jR2R3-P301L fibrils with a pseudo 21 screw symmetry in which each half of the fibrils cross-section contains two jR2R3-P301L peptides. One chain adopts a SLS fold found in 4R tauopathies that is stabilized by a second chain wrapping around the SLS fold, reminiscent of the 3-fold and 4-fold structures observed in 4R tauopathies. These jR2R3-P301L fibrils are able to template full length tau in a prion-like fashion. Significance StatementThis study presents a first step towards designing a tauopathy specific aggregation pathway by engineering a minimal tau prion building block, jR2R3, that can template and propagate distinct disease folds. We present the discovery that P301L--among the widest used mutations in cell and animal models of Alzheimers Disease--destabilizes an aggregation-prohibiting internal hairpin and enhances the local surface water structure that serves as an entropic hotspot to exert a hyper-localized effect in jR2R3. Our study suggests that P301L may be a more suitable mutation to include in modeling 4R tauopathies than for modelling Alzheimers Disease, and that mutations are powerful tools for the purpose of designing of tau prion models as therapeutic tools.

biophysics↗

bioRxiv2022

Targeting MALAT1 Augments Sensitivity to PARP Inhibition by Impairing Homologous Recombination in Prostate Cancer.

Poly(ADP-ribose) polymerase inhibitors (PARPi) have emerged as the most promising targeted therapeutic intervention for the treatment of metastatic castrate-resistant prostate cancer (mCRPC). However, the clinical utility of PARPi has been limited to a subset of patients who harbor aberrations in the homologous recombination (HR) pathway. Here, we report that targeting MALAT1, an oncogenic lncRNA, known to be elevated in advanced-stage prostate cancer (PCa) demonstrates contextual synthetic lethality with PARPi. We show that MALAT1 silencing reprograms the HR transcriptome, contriving BRCAness-like phenotype, thus enhancing sensitivity towards PARPi. Moreover, transcriptome profiles of mCRPC patients exhibit convergence between expression of MALAT1, HR pathway, and neuroendocrine markers. Mechanistically, we show that targeting MALAT1 leads to a decrease in EZH2, a member of polycomb repressor complex-2 (PRC2), which in turn upregulates the expression of RE1 Silencing Transcription Factor (REST), a key repressor of neuroendocrine differentiation. Overall, we showed that MALAT1 plays a pivotal role in maintaining genomic integrity, thereby promoting disease progression. Conclusively, our findings suggest that inhibiting MALAT1 confers PARPi sensitization in patients resistant to anti-androgens and conventional chemotherapeutics. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=195 SRC="FIGDIR/small/494272v1_ufig1.gif" ALT="Figure 1"> View larger version (70K): org.highwire.dtl.DTLVardef@80d842org.highwire.dtl.DTLVardef@f60793org.highwire.dtl.DTLVardef@6b81eforg.highwire.dtl.DTLVardef@1fa35d_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstract:C_FLOATNO The oncogenic lncRNA MALAT1 exhibits functional pleiotropy in PCa and promotes neuroendocrine differentiation. MALAT1 fosters PCa progression by modulating several hallmark oncogenic properties, such as malignant transformation, enhanced migratory capabilities, stemness, and ultimately contributes to drug resistance. MALAT1 enhances the transcriptional regulation of genes associated with homologous recombination thereby having a profound impact on the genome integrity in metastatic prostate cancer. Over the course of disease progression, it also promotes neuroendocrine trans-differentiation by depleting the levels of REST, the key repressor for NE transdifferentiation in prostate cancer. C_FIG

cancer biology↗

bioRxiv2021

Functional and comparative genome analysis reveals clade-specific genome innovations in the killer fungus Candida auris

The thermotolerant multidrug-resistant ascomycete Candida auris rapidly emerged since 2009 and simultaneously evolved in different geographical zones worldwide, causing superficial as well as systemic infections. The molecular events that orchestrated this sudden emergence of the killer fungus remain mostly elusive. Here, we identify centromeres in C. auris and related species, using a combined approach of chromatin immunoprecipitation and comparative genomic analyses. We find that C. auris and multiple other species in the Clavispora/Candida clade shared a conserved small regional centromere landscape lacking pericentromeres. Further, a centromere inactivation event led to karyotypic alterations in this species complex. Inter-species genome analysis identified several structural chromosomal changes around centromeres. In addition, centromeres are found to be rapidly evolving loci among the different geographical clades of the same species of C. auris. Finally, we reveal an evolutionary trajectory of the unique karyotype associated with clade 2 that consists of the drug susceptible isolates of C. auris.

genomics↗

bioRxiv2019

Multi-model functionalization of disease-associated PTEN missense mutations identifies multiple molecular mechanisms underlying protein dysfunction

Functional variomics provides the foundation for personalized medicine by linking genetic variation to disease expression, outcome and treatment, yet its utility is dependent on appropriate assays to evaluate mutation impact on protein function. To fully assess the effects of 106 missense and nonsense variants of PTEN associated with autism spectrum disorder, somatic cancer and PHTS, we take a deep phenotypic profiling approach using 18 assays in 5 model systems spanning diverse cellular environments ranging from molecular function to neuronal morphogenesis and behavior. Variants inducing instability occurred across the protein, resulting in partial to complete loss of function (LoF), which was well correlated across models. However, assays were selectively sensitive to variants located in substrate binding and catalytic domains, which exhibited complete LoF or dominant negativity independent of effects on stability. Our results indicate that full characterization of variant impact requires assays sensitive to instability and a range of protein functions.

genetics↗

bioRxiv2019

Early diverging fungus Mucor circinelloides lacks centromeric histone CENP-A and displays a mosaic of point and regional centromeres

Centromeres are rapidly evolving across eukaryotes, despite performing a conserved function to ensure high fidelity chromosome segregation. CENP-A chromatin is a hallmark of a functional centromere in most organisms. Due to its critical role in kinetochore architecture, the loss of CENP-A is tolerated in only a few organisms, many of which possess holocentric chromosomes. Here, we characterize the consequence of the loss of CENP-A in the fungal kingdom. Mucor circinelloides, an opportunistic human pathogen, lacks CENP-A along with the evolutionarily conserved CENP-C, but assembles a monocentric chromosome with a localized kinetochore complex throughout the cell cycle. Mis12 and Dsn1, two conserved kinetochore proteins were found to bind nine short overlapping regions, each comprising an [~]200-bp AT-rich sequence followed by a centromere-specific conserved motif that echoes the structure of budding yeast point centromeres. Resembling fungal regional centromeres, these core centromere regions are embedded in large genomic expanses devoid of genes yet marked by Grem-LINE1s, a novel retrotransposable element silenced by the Dicer-dependent RNAi pathway. Our results suggest that these hybrid features of point and regional centromeres arose from the absence of CENP-A, thus defining novel mosaic centromeres in this early-diverging fungus.

genetics↗

bioRxiv2019

Centromere-mediated chromosome break drives karyotype evolution in closely related Malassezia species

Intra-chromosomal or inter-chromosomal genomic rearrangements often lead to speciation (1). Loss or gain of a centromere leads to alterations in chromosome number in closely related species. Thus, centromeres can enable tracing the path of evolution from the ancestral to a derived state (2). The Malassezia species complex of the phylum Basiodiomycota shows remarkable diversity in chromosome number ranging between six and nine chromosomes (3-5). To understand these transitions, we experimentally identified all eight centromeres as binding sites of an evolutionarily conserved outer kinetochore protein Mis12/Mtw1 in M. sympodialis. The 3 to 5 kb centromere regions share an AT-rich, poorly transcribed core region enriched with a 12 bp consensus motif. We also mapped nine such AT-rich centromeres in M. globosa and the related species Malassezia restricta and Malassezia slooffiae. While eight predicted centromeres were found within conserved synteny blocks between these species and M. sympodialis, the remaining centromere in M. globosa (MgCEN2) or its orthologous centromere in M. slooffiae (MslCEN4) and M. restricta (MreCEN8) mapped to a synteny breakpoint compared with M. sympodialis. Taken together, we provide evidence that breakage and loss of a centromere (CEN2) in an ancestral Malassezia species possessing nine chromosomes resulted in fewer chromosomes in M. sympodialis. Strikingly, the predicted centromeres of all closely related Malassezia species map to an AT-rich core on each chromosome that also shows enrichment of the 12 bp sequence motif. We propose that centromeres are fragile AT-rich sites driving karyotype diversity through breakage and inactivation in these and other species. Significance statementThe number of chromosomes can vary between closely related species. Centromere loss destabilizes chromosomes and results in reduced number of chromosomes to drive speciation. A series of evidence from studies on various cancers suggest that an imbalance in kinetochore-microtubule attachments results in breaks at the centromeres. To understand if such events can cause chromosome number changes in nature, we studied six species of Malassezia, of which three possess eight chromosomes and others have nine chromosomes each. We find signatures of chromosome breakage at the centromeres in organisms having nine chromosomes. We propose that the break at the centromere followed by fusions of acentric chromosomes to other chromosomes could be a plausible mechanism shaping the karyotype of Malassezia and related organisms. ClassificationBiological sciences, Genetics

genomics↗