Discovery of Latent Drivers from Double Mutations in Pan-Cancer Data Reveal their Clinical Impact DOI Creative Commons
Bengi Ruken Yavuz, Chung‐Jung Tsai, Ruth Nussinov

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2021, Номер unknown

Опубликована: Апрель 4, 2021

Abstract Background Transforming patient-specific molecular data into clinical decisions is fundamental to personalized medicine. Despite massive advancements in cancer genomics, date driver mutations whose frequencies are low, and their observable transformation potential minor have escaped identification. Yet, when paired with other cis , such ‘latent driver’ can drive cancer. Here, we discover double mutations. Method We applied a statistical approach identify significantly co-occurring the pan-cancer of mutation profiles ∼80,000 tumor sequences from TCGA AACR GENIE databases. The components same gene doublets were assessed as latent drivers. merged analysis significant drug response cell lines patient derived xenografts (PDXs). This allowed us link impact information signatures for some types. Results Our comprehensive identified 228 which 113 cataloged Oncogenic activation protein be through either single or multiple independent mechanisms action. Combinations driver, weak strong leading fully activated state high rate. Tumor suppressors require higher mutational load coincide compared oncogenes implies relative robustness losing functions. Evaluation patient-derived xenograft treatment indicate that certain genes increase oncogenic activity, hence better (e.g. PIK3CA), they promote resistance drugs EGFR). Conclusion allele genome landscapes emphasizes interrogation big genomic integration results large-scale small-molecule sensitivity provide deep patterns rare; but still result dramatic phenotypic alterations,

Язык: Английский

The Mutational Landscape of Myeloid Leukaemia in Down Syndrome DOI Open Access

Carini Picardi Morais de Castro,

Maria Cadefau, Sergi Cuartero

и другие.

Cancers, Год журнала: 2021, Номер 13(16), С. 4144 - 4144

Опубликована: Авг. 18, 2021

Children with Down syndrome (DS) are particularly prone to haematopoietic disorders. Paediatric myeloid malignancies in DS occur at an unusually high frequency and generally follow a well-defined stepwise clinical evolution. First, the acquisition of mutations GATA1 transcription factor gives rise transient myeloproliferative disorder (TMD) newborns. While this condition spontaneously resolves most cases, some clones can acquire additional mutations, which trigger leukaemia (ML-DS). These secondary predominantly found chromatin epigenetic regulators—such as cohesin, CTCF or EZH2—and signalling mediators JAK/STAT RAS pathways. Most them also non-DS malignancies, albeit extremely different frequencies. Intriguingly, proteins involved three-dimensional organization genome nearly 50% cases. How resulting mutant cooperate trisomy 21 promote ML-DS is not fully understood. In review, we summarize discuss current knowledge about sequential genomic alterations ML-DS.

Язык: Английский

Процитировано

11
Multivalent polymers can control phase boundary, dynamics, and organization of liquid-liquid phase separation DOI Creative Commons

Emiko Zumbro,

Alfredo Alexander‐Katz

PLoS ONE, Год журнала: 2021, Номер 16(11), С. e0245405 - e0245405

Опубликована: Ноя. 8, 2021

Multivalent polymers are a key structural component of many biocondensates. When interacting with their cognate binding proteins, multivalent such as RNA and modular proteins have been shown to influence the liquid-liquid phase separation (LLPS) boundary both control condensate formation dynamics after separation. Much is still unknown about function these condensed droplets, but changes in or associated neurodegenerative diseases amyotrophic lateral sclerosis (ALS) Alzheimer’s Disease. Therefore, investigation into how structure relates biocondensate maturation essential understanding treating diseases. Here, we use coarse-grain, Brownian Dynamics simulation reactive that mimics specific interactions order investigate difference between non-specific polymers. We show can lead much larger droplet at lower protein-polymer interaction energies than specific, valence-limited counterparts. also demonstrate effects solvent conditions polymer length on separation, present modulating energy change organization three system polymer, protein, solvent. Finally, compare surface tension dynamics, protein solubilities higher attraction/affinity result slower dynamics. This research will help better understand experimental systems provides additional insight LLPS.

Язык: Английский

Процитировано

10
Widespread alteration of protein autoinhibition in human cancers DOI

Jorge A. Holguin-Cruz,

Jennifer M. Bui,

Ashwani Jha

и другие.

Cell Systems, Год журнала: 2024, Номер 15(3), С. 246 - 263.e7

Опубликована: Фев. 15, 2024

Язык: Английский

Процитировано

1
Cohesin composition and dosage independently affect early development in zebrafish DOI Creative Commons
Anastasia Labudina, Michael Meier,

Grégory Gimenez

и другие.

Development, Год журнала: 2024, Номер 151(15)

Опубликована: Авг. 1, 2024

Cohesin, a chromatin-associated protein complex with four core subunits (Smc1a, Smc3, Rad21 and either Stag1 or 2), has central role in cell proliferation gene expression metazoans. Human developmental disorders termed 'cohesinopathies' are characterized by germline variants of cohesin its regulators that do not entirely eliminate function. However, it is clear whether mutations individual have independent consequences. Here, we show zebrafish rad21 stag2b mutants independently influence embryonic tailbud development. Both altered mesoderm induction, but only homozygous heterozygous mutation affects cycle expression. narrower notochords reduced Wnt signaling neuromesodermal progenitors as revealed single-cell RNA sequencing. Stimulation rescues transcription morphology stag2b, rad21, mutants. Our results suggest altering the quantity versus composition consequences, implications for understanding management cohesinopathies.

Язык: Английский

Процитировано

1
High-throughput Oligopaint screen identifies druggable regulators of genome folding DOI Creative Commons
Daniel Park, Son C. Nguyen,

Randi Isenhart

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2022, Номер unknown

Опубликована: Апрель 10, 2022

Summary Although the molecular rules governing genome organization are being quickly elucidated, relatively few proteins regulating this process have been identified. To address gap, we developed a fully automated imaging pipeline, called HiDRO (high-throughput DNA or RNA labeling with optimized Oligopaints), that permits quantitative measurement of chromatin interactions across large number samples. Using HiDRO, screened human druggable and identified >300 factors regulate folding during interphase, including 43 validated hits either increase decrease between topological associating domains (TADs). We discovered genetic chemical inhibition ubiquitous kinase GSK3A enhances long-range by dysregulating cohesin-mediated looping. Collectively, these results highlight noncanonical role for signaling in nuclear architecture underscore broader utility HiDRO-based screening to identify novel mechanisms drive spatial genome.

Язык: Английский

Процитировано

6
In-vivo Single-Molecule Imaging in Yeast: Applications and Challenges DOI
Nitesh Kumar Podh, Sheetal Paliwal, Partha Dey

и другие.

Journal of Molecular Biology, Год журнала: 2021, Номер 433(22), С. 167250 - 167250

Опубликована: Сен. 17, 2021

Язык: Английский

Процитировано

7
Genetically induced redox stress occurs in a yeast model for Roberts syndrome DOI Creative Commons

Michael G. Mfarej,

Robert V. Skibbens

G3 Genes Genomes Genetics, Год журнала: 2021, Номер 12(2)

Опубликована: Дек. 13, 2021

Roberts syndrome (RBS) is a multispectrum developmental disorder characterized by severe limb, craniofacial, and organ abnormalities often intellectual disabilities. The genetic basis of RBS rooted in loss-of-function mutations the essential N-acetyltransferase ESCO2 which conserved from yeast (Eco1/Ctf7) to humans. ESCO2/Eco1 regulate many cellular processes that impact chromatin structure, chromosome transmission, gene expression, repair genome. etiology remains contentious with current models include transcriptional dysregulation or mitotic failure. Here, we report evidence supports an emerging model defective DNA damage responses. First, results reveal redox stress elevated both eco1 cohesion factor Saccharomyces cerevisiae mutant cells. Second, provide Eco1 factors are required for oxidative such ECO1 cohesin result reduced cell viability hyperactivation checkpoints occur response stress. Moreover, show mutation solely sufficient induce endogenous sensitizes cells exogenous genotoxic challenges. Remarkably, antioxidant treatment desensitizes range damaging agents, raising possibility modulating state may represent important avenue tumors bear mutations.

Язык: Английский

Процитировано

6
Comprehensive Analysis of SMC Gene Family Prognostic Value and Immune Infiltration in Patients With Pancreatic Adenocarcinoma DOI Creative Commons
Hui Nie,

Yanhao Wu,

Chunlin Ou

и другие.

Frontiers in Medicine, Год журнала: 2022, Номер 9

Опубликована: Март 15, 2022

Pancreatic adenocarcinoma (PAAD) is a malignant tumor with high morbidity and mortality worldwide. Members from the structural maintenance of chromosomes (SMC) gene family function as oncogenes in various types, but their roles PAAD have not been elucidated. In this study, we aimed to explore role SMC progression cancer immune infiltration using integrative bioinformatic analyses. The results showed that 1A, 2, 3, 4, 6 were overexpressed tissues; these, 5, could be potential prognostic biomarkers for PAAD. expression genes was found strongly associated cell infiltration. According infiltrative status cells, mRNA overall recurrence-free survival patients. conclusion, may involved tumorigenesis cancer-immune interactions; thus, members serve promising therapeutic

Язык: Английский

Процитировано

4
Cohesin: an emerging master regulator at the heart of cardiac development DOI

Michael G. Mfarej,

Caitlin Hyland,

Annie C. Sanchez

и другие.

Molecular Biology of the Cell, Год журнала: 2023, Номер 34(5)

Опубликована: Март 22, 2023

Cohesins are ATPase complexes that play central roles in cellular processes such as chromosome division, DNA repair, and gene expression. Cohesinopathies arise from mutations cohesin proteins or complex regulators encompass a family of related developmental disorders present with range severe birth defects, affect many different physiological systems, often lead to embryonic fatality. Treatments for cohesinopathies limited, large part due the lack understanding biology. Thus, characterizing signaling networks lie upstream downstream cohesin-dependent pathways remains clinically relevant. Here, we highlight alterations cohesins result cohesinopathies, focus on cardiac defects. In addition, suggest novel more unifying view regarding mechanisms through which cohesinopathy-based heart defects may arise.

Язык: Английский

Процитировано

2
Down syndrome and leukemia: An insight into the disease biology and current treatment options DOI
Sonali P. Barwe, E. Anders Kolb, Anilkumar Gopalakrishnapillai

и другие.

Blood Reviews, Год журнала: 2023, Номер 64, С. 101154 - 101154

Опубликована: Ноя. 25, 2023

Язык: Английский

Процитировано

2