Biology subjects

Zhang, T.

Publications and source records attributed to Zhang, T..

At least 595 records · Page 33Linked to original sources

bioRxiv2019

A light-dependent molecular link between competition cues and defense responses in plants

One of the principal internal signals controlling plant growth and defense is jasmonate (JA), a potent growth inhibitor that is simultaneously a central regulator of plant immunity to herbivores and pathogens. When shade-intolerant plants perceive the proximity of competitors using the photoreceptor phytochrome B (phyB), they accelerate growth and down-regulate JA responses. However, the mechanisms by which photoreceptors relay light cues to the JA signaling pathway are not understood. Here we identify a sulfotransferase (ST2a) that is strongly up-regulated by plant proximity perceived by phyB via the phyB-Phytochrome Interacting Factor (PIF) signaling module. By catalyzing the formation of a sulfated JA derivative, ST2a acts to degrade bioactive forms of JA and represents a direct molecular link between photoreceptors and hormone signaling in plants. The enzyme provides a molecular mechanism for prioritizing shade avoidance over defense under close plant competition.

plant biology↗

bioRxiv2019

Actin chromobody imaging reveals sub-organellar actin dynamics

The actin cytoskeleton plays multiple critical roles in cells, from cell migration to organelle dynamics. The small and transient actin structures regulating organelle dynamics are difficult to detect with fluorescence microscopy. We developed an approach using fluorescent protein-tagged actin nanobodies targeted to organelle membranes to enable live cell imaging of sub-organellar actin dynamics with unprecedented spatiotemporal resolution. These probes reveal that ER-associated actin drives fission of multiple organelles including mitochondria, endosomes, lysosomes, peroxisomes, and the Golgi.\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC=\"FIGDIR/small/639278v2_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (46K):\norg.highwire.dtl.DTLVardef@18851e1org.highwire.dtl.DTLVardef@b7c608org.highwire.dtl.DTLVardef@12a7629org.highwire.dtl.DTLVardef@b39a0a_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2019

GENETIC RESILIENCE OF A ONCE ENDANGERED SPECIES, TIBETAN ANTELOPE (Pantholops hodgsonii)

Population reduction is generally assumed to reduce the populations genetic diversity and hence its ability to adapt to environmental change. However, if life history traits that promote gene flow buffer populations from such impacts, conservation efforts should aim to maintain those traits in vulnerable species. Tibetan antelope (Pantholops hodgsonii) has experienced population reduction by 95% due to poaching during the 20th century. We hypothesize that opportunities for gene flow provided by their sex-specific migration buffered their genetic diversity from the poaching impacts. We measured the mtDNA (control region, CR) and nuDNA (microsatellites or STRs) diversity, population differentiation, along with the change in effective population size (pre-poaching era vs. post-poaching era) and tested for a genetic bottleneck. Our results showed that Tibetan antelope maintained considerable genetic diversity in both mtDNA CR and STR markers (Hd = 0.9970 and Hobs = 0.8446, respectively), despite a marked reduction in post-poaching effective population size 368.9 (95% CI of 249.3 - 660.6) compared to the pre-poaching average (4.93x103 - 4.17x104). Post-poached populations also had low population structure and showed no evidence of a genetic bottleneck. Pairwise Fst values using CR haplotype frequencies were higher than those using STR allele frequencies, suggesting different degrees of gene flow mediated by females and males. This study suggests that the Tibetan antelopes sex-specific migration buffered their loss of genetic diversity in the face of severe demographic decline. These findings highlight the importance of recognizing the traits likely to maintain genetic diversity and promoting conservation efforts that allow them to be exercised. For Tibetan antelope, this requires assuring that their migration routes remain unobstructed by growing human disturbances while continuing to enforce anti-poaching law enforcement efforts.

genetics↗

bioRxiv2019

Investigating Fibroblast-Induced Collagen Gel Contraction Using a Dynamic Microscale Platform

Mechanical forces have long been recognized as fundamental drivers in biological processes, such as embryogenesis, tissue formation and disease regulation. The collagen gel contraction (CGC) assay has served as a classic tool in the field of mechanobiology to study cell-induced contraction of extracellular matrix (ECM), which plays an important role in inflammation and wound healing. In a conventional CGC assay, cell-laden collagen is loaded into a cell culture vessel (typically a well plate) and forms a disk-shaped gel adhering to the bottom of the vessel. The decrement in diameter or surface area of the gel is used as a parameter to quantify the degree of cell contractility. In this study, we developed a microscale CGC assay with an engineered well plate insert that uses surface tension forces to load and manipulate small volumes (14 {micro}L) of cell-laden collagen. The system is easily operated with two pipetting steps and the microscale device moves dynamically as a result of cellular forces. We used a straightforward one-dimensional measurement as the gel contraction readout. We adapted a conventional lung fibroblast CGC assay to demonstrate the functionality of the device, observing significantly more gel contraction when human lung fibroblasts were cultured in serum-containing media versus serum-free media (p[≤]0.01). We further cocultured eosinophils and fibroblasts in the system, two important cellular components that lead to fibrosis in asthma, and observed that soluble factors from eosinophils significantly increase fibroblast-mediated gel contraction (p[≤]0.01). Our microscale CGC device provides a new method for studying downstream ECM effects of intercellular cross talk using 7-35 fold less cell-laden gel than traditional CGC assays.

cell biology↗

bioRxiv2019

Prostate-Specific Antigen Dynamics Predict Individual Responses to Intermittent Androgen Deprivation

BackgroundIntermittent androgen deprivation therapy (IADT) is an attractive treatment approach for biochemically recurrent prostate cancer (PCa), whereby cycling treatment on and off can reduce cumulative dose, limit toxicities, and delay development of treatment resistance. To optimize treatment within the context of ongoing intratumoral evolution, underlying mechanisms of resistance and actionable biomarkers need to be identified.\n\nMethodsWe have developed a quantitative framework to simulate enrichment of prostate cancer stem cell (PCaSC) dynamics during treatment as a plausible mechanism of resistance evolution.\n\nResultsSimulated dynamics of PCaSC and non-stem cancer cells demonstrate that stem cell proliferation patterns correlate with longitudinal serum prostate-specific antigen (PSA) measurements in 70 PCa patients undergoing multiple cycles of IADT. By learning the dynamics from each treatment cycle, individual model simulations predict evolution of resistance in the subsequent IADT cycle with a sensitivity and specificity of 57% and 94%, respectively and an overall accuracy of 90%. Additionally, we evaluated the potential benefit of docetaxel for IADT in biochemically recurrent PCa. Model simulations based on response dynamics from the first IADT cycle identify patients who would or would not benefit from concurrent docetaxel in subsequent cycles.\n\nConclusionOur results demonstrate the feasibility and potential value of adaptive clinical trials guided by patient-specific mathematical models of intratumoral evolutionary dynamics continuously updated with each treatment cycle.\n\nTranslational RelevanceCompared to continuous androgen deprivation therapy, intermittent androgen deprivation (IADT) has been shown to reduce toxicity and delay time to progression in prostate cancer. While numerous mathematical models have been developed to study the response to both continuous and intermittent androgen deprivation, very few have identified actionable biomarkers of resistance and exploited them to predict how patients will or will not respond to subsequent treatment. Here, we identify prostate-specific antigen (PSA) dynamics as the first such biomarker. Mechanistic mathematical modeling of prostate cancer stem cell dynamics that dictate prostate-specific antigen serum levels predicts individual responses to IADT with 90% overall accuracy and can be used to develop patient-specific adaptive treatment protocols, and potentially identify patients that may benefit from concurrent chemotherapy. Model results demonstrate the feasibility and potential value of adaptive clinical trials guided by patient-specific mathematical models of intratumoral evolutionary dynamics continuously updated with each treatment cycle.

cancer biology↗

bioRxiv2019

Massively parallel reporter assays combined with cell-type specific eQTL informed multiple melanoma loci and identified a pleiotropic function of HIV-1 restriction gene, MX2, in melanoma promotion

Genome-wide association studies (GWAS) have identified [~]20 melanoma susceptibility loci. To identify susceptibility genes and variants simultaneously from multiple GWAS loci, we integrated massively-parallel reporter assays (MPRA) with cell type-specific epigenomic data as well as melanocyte-specific expression quantitative trait loci (eQTL) profiling. Starting from 16 melanoma loci, we selected 832 variants overlapping active regions of chromatin in cells of melanocytic lineage and identified 39 candidate functional variants displaying allelic transcriptional activity by MPRA. For four of these loci, we further identified four colocalizing melanocyte cis-eQTL genes (CTSS, CASP8, MX2, and MAFF) matching the allelic activity of MPRA functional variants. Among these, we further characterized the locus encompassing the HIV-1 restriction gene, MX2, on chromosome band Chr21q22.3 and validated a functional variant, rs398206, among multiple high LD variants. rs398206 mediates allelic transcriptional activity via binding of the transcription factor, YY1. This allelic transcriptional regulation is consistent with a significant cis-eQTL of MX2 in primary human melanocytes, where the melanoma risk-associated A allele of rs398206 is correlated with higher MX2 levels. Melanocyte-specific transgenic expression of human MX2 in a zebrafish model demonstrated accelerated melanoma formation in a BRAFV600E background. Thus, using an efficient scalable approach to streamline GWAS follow-up functional studies, we identified multiple candidate melanoma susceptibility genes and variants, and uncovered a pleiotropic function of MX2 in melanoma susceptibility.

genomics↗

bioRxiv2019

xml2jupyter: Mapping parameters between XML and Jupyter widgets

Jupyter Notebooks [4, 6] provide executable documents (in a variety of programming languages) that can be run in a web browser. When a notebook contains graphical widgets, it becomes an easy-to-use graphical user interface (GUI). Many scientific simulation packages use text-based configuration files to provide parameter values and run at the command line without a graphical interface. Manually editing these files to explore how different values affect a simulation can be burdensome for technical users, and impossible to use for those with other scientific backgrounds. xml2jupyter is a Python package that addresses these scientific bottlenecks. It provides a mapping between configuration files, formatted in the Extensible Markup Language (XML), and Jupyter widgets. Widgets are automatically generated from the XML file and these can, optionally, be incorporated into a larger GUI for a simulation package, and optionally hosted on cloud resources. Users modify parameter values via the widgets, and the values are written to the XML configuration file which is input to the simulations command-line interface. xml2jupyter has been tested using PhysiCell [1], an open source, agent-based simulator for biology, and it is being used by students for classroom and research projects. In addition, we use xml2jupyter to help create Jupyter GUIs for PhysiCell-related applications running on nanoHUB [5].

bioinformatics↗

bioRxiv2019

Characterization of novel Chrysosporium morrisgordonii sp. nov., from bat white-nose syndrome (WNS) affected mines, northeastern United States

Psychrotolerant hyphomycetes including unrecognized taxon are commonly found in bat hibernation sites in Upstate New York. During a mycobiome survey, a new fungal species, Chrysosporium morrisgordonii sp. nov., was isolated from bat White-nose syndrome (WNS) afflicted Graphite mine in Warren County, New York. This taxon was distinguished by its ability to grow at low temperature spectra from 6{degrees}C to 25{degrees}C. Conidia were tuberculate and thick-walled, globose to subglobose, unicellular, 3.5-4.6 {micro}m x3.5-4.6 {micro}m, sessile or borne on narrow stalks. The stalks occurred at right angles to the hypha. Intercalary aleuroconidia were also observed; the hyphae were septate, hyaline, smooth-walled, 1-3 {micro}m wide, straight or branched. The ITS1-5.8S-ITS2 sequence of C. morrisgordonii differed from the closest match to C. speluncarum by 37 nucleotides (94% identity); the Neighbor-joining phylogenetic tree confirmed that C. morrisgordonii was placed in a well-supported monophyletic group with C. speluncarum. LSU and ITS phylogenetic trees further indicated that C. morrisgordonii, C. speluncarum, Renispora flavissima, Neogymnomyces virgineus and Gymnoascus demonbreunii formed a distinct group in the Onygenales.

microbiology↗

bioRxiv2019

Folate deficiency facilitates coordination of KDM6A with p53 in response to DNA damage

Folate contributes to the accumulation of DNA strand breaks (DSBs) in the genome. Kdm6a plays a critical role in early embryogenesis but it is unknown whether Kdm6a is involved in the DNA damage response under folate deficiency. Here, we established a low folate environment for mouse embryonic cells using a folate antagonist (methotrexate, MTX). We found increased enrichment of DSBs in Kdm6a in MTX-treated cells, resulting in reduced Kdm6a expression. MTX treatment enriched KDM6A in the nonhomologous end-joining (NHEJ) repair pathway and controlled the expression of the Ku heterodimer (Ku70/80) and XRCC4. The activation of NHEJ repair pathway-associated genes under folate deficiency relied on the specific interaction between KDM6A and p53. p53 silencing increased Ku heterodimer expression. In addition, in a neural tube defect (NTD) mouse model and low folate neural tube defect human brain samples, KDM6A levels were also decreased and accompanied by over-expression of Ku80. Our findings highlight how alterations in folate levels affect KDM6A with respect to DNA breakage and DNA repair, offering a new insight into the molecular function of KDM6A.\n\nSummary statementOur study demonstrates for the first time that in mammals, Kdm6a and p53 have synergistic effects during DNA fragmentation repair.

bioinformatics↗

bioRxiv2019

A Chemical Probe of CARM1 Alters Epigenetic Plasticity against Breast Cancer Cell Invasion

CARM1 is a cancer-relevant protein arginine methyltransferase that regulates many aspects of transcription. Its pharmacological inhibition is a promising anti-cancer strategy. Here SKI-73 is presented as a CARM1 chemical probe with pro-drug properties. SKI-73 can rapidly penetrate cell membranes and then be processed into active inhibitors, which are retained intracellularly with 10-fold enrichment for days. These compounds were characterized for their potency, selectivity, modes of action, and on-target engagement. SKI-73 recapitulates the effect of CARM1 knockout against breast cancer cell invasion. Single-cell RNA-seq analysis revealed that the SKI-73-associated reduction of invasiveness act via altering epigenetic plasticity and suppressing the invasion-prone subpopulation. Interestingly, SKI-73 and CARM1 knockout alter the epigenetic plasticity with remarkable difference, arguing distinct modes of action between the small-molecule and genetic perturbation. We therefore discovered a CARM1-addiction mechanism of cancer metastasis and developed a chemical probe to target this process.

biochemistry↗

bioRxiv2019

Extensive adaptive immune response of AAVs and Cas proteins in non-human primates

The CRISPR-mediated Cas system is the most widely used tool in gene editing and gene therapy for its convenience and efficiency. Delivery of the CRISPR system by adeno-associated viruses (AAVs) is currently the most promising approach to gene therapy. However, pre-existing adaptive immune responses against CRISPR nuclease (PAIR-C) and AAVs has been found in human serum, indicating that immune response is a problem that cannot be ignored, especially for in vivo gene correction. Non-human primates (NHPs) share many genetic and physiological traits with human, and are considered as the bridge for translational medicine. However, whether NHPs have same PAIR-C status with human is still unknown. Here, macaques (rhesus and cynomolgus), including normal housed and CRISPR-SpCas9 or TALENs edited individuals, were used to detect PAIR-C which covered SaCas9, SpCas9, AsCas12a and LbCas12a. Dogs and mice were also detected to expand the range of species. In addition, pre-existing adaptive antibodies to AAV8 and AAV9 were performed against macaques of different ages. The results showed that adaptive immunity was pre-existing in the macaques regardless of Cas proteins and AAVs. These findings indicate that the pre-existing adaptive immune of AAV-delivered CRISPR construction and correction system should be concerned for in vivo experiments.

immunology↗

bioRxiv2019

A multi-omic cohort as a reference point for promoting a healthy human gut microbiome

More than a decade of gut microbiome studies have a common goal for human health. As most of the disease studies sample the elderly or the middle-aged, a reference cohort for young individuals has been lacking. It is also not clear what other omics data need to be measured to better understand the gut microbiome. Here we present high-depth metagenomic shotgun sequencing data for the fecal microbiome together with other omics data in a cohort of 2,183 adults, and observe a number of vitamins, hormones, amino acids and trace elements to correlate with the gut microbiome and cluster with T cell receptors. Associations with physical fitness, sleeping habits and dairy consumption are identified in this large multi-omic cohort. Many of the associations are validated in an additional cohort of 1,404 individuals. Our comprehensive data are poised to advise future study designs to better understand and manage our gut microbiome both in population and in mechanistic investigations.

microbiology↗

bioRxiv2019

Oral immunization with a probiotic cholera vaccine induces broad protective immunity against Vibrio cholerae colonization and disease in mice

Oral cholera vaccines (OCVs) are being increasingly employed, but current killed formulations generally require multiple doses and lack efficacy in young children. We recently developed a new live-attenuated OCV candidate (HaitiV) derived from a Vibrio cholerae strain isolated during the 2010 Haiti cholera epidemic. HaitiV exhibited an unexpected probiotic-like activity in infant rabbits, preventing intestinal colonization and disease by wild-type V. cholerae before the onset of adaptive immunity. However, it remained unknown whether HaitiV would behave similarly to other OCVs to stimulate adaptive immunity against V. cholerae. Here, we orally immunized adult germ-free female mice to test HaitiVs immunogenicity. HaitiV safely and stably colonized vaccinated mice and induced known adaptive immune correlates of cholera protection within 14 days of administration. Pups born to immunized mice were protected against lethal challenges of both homologous and heterologous V. cholerae strains. Cross-fostering experiments revealed that protection was not dependent on vaccine colonization in or transmission to the pups. These findings demonstrate the protective immunogenicity of HaitiV and support its development as a new tool for limiting cholera. Author summaryVaccines for cholera are gaining acceptance as public health tools for prevention of cholera and curtailing the spread of outbreaks. However, current killed vaccines provide minimal protection in young children, who are especially susceptible to this diarrheal disease, and do not stimulate immunity against antigens that may only be expressed by live bacteria during infection. We recently developed HaitiV, an extensively engineered live-attenuated oral cholera vaccine candidate, derived from a clinical isolate from the Haiti cholera outbreak. Here, we found that the HaitiV induces immunological correlates of protection against cholera in germ free mice and leads to protection against disease in their offspring. Protection in this model was dependent on passively acquired factors in the milk of immunized dams and not transmission or colonization of HaitiV. Coupling the immunogenicity data presented here with our previous observation that HaitiV can protect from cholera prior to the induction of adaptive immunity, suggests that HaitiV may provide both rapid-onset short-term protection from disease while eliciting stable and long-lasting immunity against cholera.

microbiology↗

bioRxiv2019

Selection for antibiotic resistance is reduced when embedded in a natural microbial community

Antibiotic resistance has emerged as one of the most pressing, global threats to public health. In single-species experiments selection for antibiotic resistance occurs at very low antibiotic concentrations. However, it is unclear how far these findings can be extrapolated to natural environments, where species are embedded within complex communities. We competed isogenic strains of Escherichia coli, differing exclusively in a single chromosomal resistance determinant, in the presence and absence of a pig fecal microbial community across a gradient of antibiotic concentration for two relevant antibiotics: gentamicin and kanamycin. We show that the minimal selective concentration was increased by more than one order of magnitude for both antibiotics when embedded in the community. We identified two general mechanisms were responsible for the increase in minimal selective concentration: an increase in the cost of resistance and a protective effect of the community for the susceptible phenotype. These findings have implications for our understanding of the evolution and selection of antibiotic resistance, and can inform future risk assessment efforts on antibiotic concentrations.

microbiology↗

bioRxiv2019

Immune gene expression profiling reveals heterogeneity in luminal breast tumors

Disease heterogeneity of immune gene expression patterns of luminal breast cancer (BC) has not been well studied. We performed immune gene expression profiling of tumor and adjacent normal tissue in 92 Asian luminal BC patients and identified three distinct immune subtypes. Tumors in one subtype exhibited signs of T-cell activation, lower ESR1/ESR2 expression ratio and higher expression of immune checkpoint genes, nonsynonymous mutation burden, APOBEC-signature mutations, and increasing body mass index compared to other luminal tumors. Tumors in a second subtype were characterized by increased expression of interferon-stimulated genes and enrichment for TP53 somatic mutations. The presence of three immune subtypes within luminal BC was replicated in cases drawn from The Cancer Genome Atlas and a Korean breast cancer study. Our findings suggest that immune gene expression and associated genomic features could be useful to further stratify luminal BC beyond the current luminal A/B classification.

genomics↗

bioRxiv2019

Time- and size-resolved bacterial aerosol dynamics in highly polluted air: new clues for haze formation mechanism

Aerosol chemistry is often studied without considering microbial involvements. Here, we have applied a high-volume (1 m3/min) aerosol sampler and the Micro-Orifice Uniform Deposit Impactor (NanoMoudi) along with molecular and microscopic methods to investigate time-and size-resolved bacterial aerosol dynamics in air. Under high particulate matter (PM) polluted episodes, bacterial aerosols were detected to have a viability up to 50-70% in the 0.56-1 m size range, at which elevated levels of SO42-, NO3- and NH4+ were concurrently observed. Engineered or acclimated for both pharmaceuticals and wastewater treatment, bacteria such as Psychrobacter spp., Massilia spp., Acinetobacter lwoffii, Exiguobacterium aurantiacum, and Bacillus megaterium were shown to have experienced massive abundance shifts in polluted air on early mornings and late afternoons, on which were previously reported to witness rapid new particle formation events. For example, Acinetobacter spp. were shown to account for > 96% abundance at a corresponding PM2.5 level of 208 ng/m3. The bacterial aerosol changes corresponded to the observed PM2.5 mass peak shift from 3.2-5.6 m to the high viability size range of 0.56-1m. Additionally, it is interesting that elevated levels of soluble Na, Ca, Mg, K, Al, Fe and P elements that are required for bacterial growth were observed to co-occur with those significant bacterial aerosol structure shifts in the air. For particular time-resolved PM2.5 pollution episodes, Acinetobacter and Massilia were shown to alternate in dominating the time-resolved aerosol community structures. The results from a HYSPLIT trajectory model simulation suggested that the role by air mass transport in affecting the observed bacterial aerosol dynamics could be minor. As an evidence, we found that Acinetobacter, Psychrobacter, Exiguobacterium, and Bacillus genera were emitted into the air with a level of > 3000 CFU/m3 from a pharmaceutical plant. In addition, high level of VOCs up to 15,030 ppbv, mainly Acetone (61%) and Acetaldehyde (11%), were also detected in the air inside the plant. All the data including size-resolved viability and time-resolved bacterial aerosol dynamics together with their growth conditions detected in the air suggested that airborne bacteria in the size range of 0.56- 1m could have played important roles for haze formation in Beijing. The results about time- and size-resolved bacterial aerosol dynamics from this work provide a fresh understanding of aerosol chemistry especially in highly polluted air. It is hoped that these findings could lend a support in future cost-effective air pollution control practices.

microbiology↗

bioRxiv2018

Lasagna: Multifaceted Protein-Protein Interaction Prediction Based on Siamese Residual RCNN

Sequence-based protein-protein interaction (PPI) prediction represents a fundamental computational biology problem. To address this problem, extensive research efforts have been made to extract predefined features from the sequences. Based on these features, statistical algorithms are learned to classify the PPIs. However, such explicit features are usually costly to extract, and typically have limited coverage on the PPI information. Hence, we present an end-to-end framework, Lasagna, for PPI predictions using only the primary sequences of a protein pair. Lasagna incorporates a deep residual recurrent convolutional neural network in the Siamese learning architecture, which leverages both robust local features and contextualized information that are significant for capturing the mutual influence of protein sequences. Our framework relieves the data pre-processing efforts that are required by other systems, and generalizes well to different application scenarios. Experimental evaluations show that Lasagna outperforms various state-of-the-art systems on the binary PPI prediction problem. Moreover, it shows a promising performance on more challenging problems of interaction type prediction and binding affinity estimation, where existing approaches fall short. The implementation of our framework is available at https://github.com/muhaochen/seq_ppi.git

bioinformatics↗

bioRxiv2018

CDK12 loss in cancer cells affects DNA damage response genes through premature cleavage and polyadenylation

The cyclin-dependent kinase 12 (CDK12) modulates transcription elongation by phosphorylating the carboxy-terminal domain of RNA polymerase II and appears to selectively affect the expression of DNA damage response (DDR) and mRNA processing genes. Yet, the mechanism(s) by which it achieves this selectivity remains unclear. Using a highly selective CDK12/13 inhibitor, THZ531, and nascent RNA sequencing, we show that CDK12 inhibition results in gene length-dependent elongation defects, leading to premature cleavage and polyadenylation (PCPA) as well as loss of expression of long (>45 kb) genes, a substantial proportion of which participate in the DDR. This early termination phenotype correlated with an increased proportion of intronic polyadenylation sites, a feature that was especially prominent among DDR genes. Finally, phosphoproteomic analysis indicated that pre-mRNA processing factors, including those involved in PCPA, are direct phosphotargets of CDKs 12 and 13. These results support a model in which DDR genes are uniquely susceptible to CDK12 inhibition due primarily to their relatively longer lengths and lower ratios of U1 snRNP binding to intronic polyadenylation sites.

cancer biology↗