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Hyperactive CDK2 Activity in Basal-like Breast Cancer Imposes a Genome Integrity Liability that can be Exploited by Targeting DNA Polymerase Epsilon

ABSTRACT: RNAseq data for MDA-MB-231, CAMA-1, and MCF7 cells expressing shPOLE and either a vector control or cDNA POLE rescue

ORGANISM(S): Homo sapiens

PROVIDER: GSE159052 | GEO | 2020/10/06

REPOSITORIES: GEO

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Hyperactive CDK2 Activity in Basal-like Breast Cancer Imposes a Genome Integrity Liability that Can Be Exploited by Targeting DNA Polymerase ε.

Project description:Knowledge of fundamental differences between breast cancer subtypes has driven therapeutic advances; however, basal-like breast cancer (BLBC) remains clinically intractable. Because BLBC exhibits alterations in DNA repair enzymes and cell-cycle checkpoints, elucidation of factors enabling the genomic instability present in this subtype has the potential to reveal novel anti-cancer strategies. Here, we demonstrate that BLBC is especially sensitive to suppression of iron-sulfur cluster (ISC) biosynthesis and identify DNA polymerase epsilon (POLE) as an ISC-containing protein that underlies this phenotype. In BLBC cells, POLE suppression leads to replication fork stalling, DNA damage, and a senescence-like state or cell death. In contrast, luminal breast cancer and non-transformed mammary cells maintain viability upon POLE suppression but become dependent upon an ATR/CHK1/CDC25A/CDK2 DNA damage response axis. We find that CDK1/2 targets exhibit hyperphosphorylation selectively in BLBC tumors, indicating that CDK2 hyperactivity is a genome integrity vulnerability exploitable by targeting POLE.

| S-EPMC7687292 | biostudies-literature

Hyperactive CDK2 Activity in Basal-like Breast Cancer Imposes a Genome Integrity Liability that can be Exploited by Targeting DNA Polymerase Epsilon

Project description:Hyperactive CDK2 Activity in Basal-like Breast Cancer Imposes a Genome Integrity Liability that can be Exploited by Targeting DNA Polymerase Epsilon

| PRJNA667486 | ENA

The CIC::DUX4 oncoprotein maintains DNA integrity through direct regulation of the catalytic subunit of DNA polymerase epsilon (POLE).

Project description:Transcription factor (TF) fusion oncoproteins represent cancer specific alterations that arise from chromosomal rearrangements. Through target gene recognition, TF fusions can disseminate transcriptional responses that collectively work to drive tumorigenesis. Thus, identifying the molecular targets that operate as a disease driving network can potentially uncover key actionable dependencies. We have taken this strategy to dissect the underlying biological mechanism by which CIC::DUX4, a fusion oncoprotein associated with dismal outcomes, drives sarcomagenesis. We and others have defined a CIC::DUX4 fusion mediated network that dysregulates cell-cycle and DNA replication checkpoints. Specifically, CIC::DUX4-mediated CCNE1 upregulation compromises the G1/S transition leading to high DNA replication stress and conferring a dependence on the G2/M checkpoint kinase, WEE1. Thus, WEE1 provides a molecular brake to enable effective DNA repair prior to mitotic entry. Importantly, the mechanism by which CIC::DUX4 regulates DNA repair remains unknown. Here we show that the catalytic subunit of DNA polymerase epsilon (POLE) is essential for DNA integrity and cellular division in CIC::DUX4 sarcoma. Mechanistically, POLE loss increases DNA damage and induces p21-mediated cellular senescence to limit CIC:DUX4 mediated tumor growth in vitro and tumor formation in vivo. Altogether, we credential POLE as a CIC::DUX4 target and further characterize a functional network through which CIC::DUX4 operates to drive tumor progression and survival.

2024-10-16 | GSE279467 | GEO

Modeling cancer-associated mutations reveals an integrated role for the Pol epsilon catalytic core in replisome assembly and DNA synthesis

Project description:DNA polymerase epsilon (Pol epsilon) plays multiple roles in genome duplication and its catalytic subunit POLE suppresses tumorigenesis in humans. Despite its importance, we have limited understanding of Pol epsilon functional mechanisms and how its loss-of-function affects the evolution of cancer genomes. To address this issue, we used the budding yeast ortholog Pol2 to model cancer-associated POLE mutations that affect an uncharacterized yet highly conserved Pol2/POLE family-specific region. Analysis of pol2 mutants revealed an unexpected role for this region in the incorporation of Pol epsilon into the pre-loading complex during replisome assembly. Cellular and reconstitution experiments further identified a separate role for this region in promoting Pol epsilon polymerase activity. Unlike previously reported POLE mutations leading to hypermutation in cancer cells, the examined pol2 variants increase gross chromosomal rearrangements but not mutation rates. Our findings thus suggest that the Pol epsilon catalytic core integrates replisome assembly and DNA polymerization functions and that POLE tumor suppressive roles likely extend beyond limiting replication errors.

2020-03-29 | GSE132450 | GEO

Expression of the cancer-associated DNA polymerase epsilon P286R in fission yeast leads to translesion polymerase dependent hypermutation and defective DNA replication

Project description:Somatic mutations in the proofreading domain of the replicative DNA polymerase epsilon (POLE-exonuclease domain mutations, POLE-EDMs) are frequently found in colorectal and endometrial cancers and, occasionally, in other tumours. POLE-associated cancers typically display hypermutation, microsatellite stability and a unique mutational signature, with predominance of C > A transversions in the context TCT. To understand better the contribution of hypermutagenesis to tumour development, we have modelled the most recurrent POLE-EDM (POLE-P286R) in Schizosaccharomyces pombe. Whole-genome sequencing analysis revealed that the corresponding pol2-P287R also has a strong mutator effect in vivo, with high frequency of base substitutions and relatively few frameshift mutations. The mutations are equally distributed across different genomic regions, but they occur within an AT-rich context. The most abundant mutations are TCT > TAT transversions and, in contrast to human, TCG > TTG transitions are not elevated, likely due to the absence of cytosine methylation in fission yeast. The high mutation burden of pol2-P287R leads to increased sensitivity to elevated dNTP levels and DNA damaging agents and a phenotype that is exacerbated by depletion of the Pfh1 helicase. In addition, S phase is aberrant and RPA foci are elevated, suggestive of persistent ssDNA or DNA damage, and pol2-P287R shows synthetic lethality with rad3 deletion, indicative of checkpoint activation. Significantly, deletion of translesion polymerases kappa and eta partially suppresses pol2-P287R hypermutation, indicating that both enzymes contribute to this phenotype.

2021-06-11 | GSE169231 | GEO

A recurrent cancer-associated substitution in DNA polymerase ε produces a hyperactive enzyme.

Project description:Alterations in the exonuclease domain of DNA polymerase ε (Polε) cause ultramutated tumors. Severe mutator effects of the most common variant, Polε-P286R, modeled in yeast suggested that its pathogenicity involves yet unknown mechanisms beyond simple proofreading deficiency. We show that, despite producing a catastrophic amount of replication errors in vivo, the yeast Polε-P286R analog retains partial exonuclease activity and is more accurate than exonuclease-dead Polε. The major consequence of the arginine substitution is a dramatically increased DNA polymerase activity. This is manifested as a superior ability to copy synthetic and natural templates, extend mismatched primer termini, and bypass secondary DNA structures. We discuss a model wherein the cancer-associated substitution limits access of the 3'-terminus to the exonuclease site and promotes binding at the polymerase site, thus stimulating polymerization. We propose that the ultramutator effect results from increased polymerase activity amplifying the contribution of Polε errors to the genomic mutation rate.

| S-EPMC6343027 | biostudies-literature

Mapping corticocortical structural integrity in schizophrenia and effects of genetic liability.

Project description:BackgroundStructural and diffusion tensor imaging studies implicate gray and white matter (WM) abnormalities and disruptions of neural circuitry in schizophrenia. However, the structural integrity of the superficial WM, comprising short-range association (U-fibers) and intracortical axons, has not been investigated in schizophrenia.MethodsHigh-resolution structural and diffusion tensor images and sophisticated cortical pattern matching methods were used to measure and compare global and local variations in superficial WM fractional anisotropy between schizophrenia patients and their relatives and community comparison subjects and their relatives (n = 150).ResultsCompared with control subjects, patients showed reduced superficial WM fractional anisotropy distributed across each hemisphere, particularly in left temporal and bilateral occipital regions (all p < .05, corrected). Furthermore, by modeling biological risk for schizophrenia in patients, patient relatives, and control subjects, fractional anisotropy was shown to vary in accordance with relatedness to a patient in both hemispheres and in the temporal and occipital lobes (p < .05, corrected). However, effects did not survive correction procedures for two-group comparisons between patient relatives and control subjects.ConclusionsResults extend previous findings restricted to deep WM pathways to demonstrate that disturbances in corticocortical connectivity are associated with schizophrenia and might indicate a genetic predisposition for the disorder. Because the structural integrity of WM plays a crucial role in the functionality of networks linking gray matter regions, disturbances in the coherence and organization of fibers at the juncture of the neuropil might relate to features of schizophrenia at least partially attributable to disease-related genetic factors.

| S-EPMC3838300 | biostudies-literature

Therapeutic efficacy of INX-315, a selective CDK2 inhibitor, in solid tumors [MCF7 and T47D RNAseq]

Project description:We performed RNA sequencing on T47D and MCF7 cells, both parental and abema- or abema/fulvestrant- resistant, treated with either control vehicle or 300 nM (MCF7) or 100 nM (T47D) INX-315 for 7 days

2023-11-22 | GSE243150 | GEO

Therapeutic efficacy of INX-315, a selective CDK2 inhibitor, in solid tumors [MCF7 ATACseq]

Project description:We performed the Assay for Transposase-Accessible Chromatin with Sequencing (ATAC-Seq) on (i) parental MCF7 cells treated with control vehicle or abemaciclib (ii) abemaciclib- and abemaciclib/fulvestrant-resistant cells treated with control vehicle or INX-315.

2023-11-22 | GSE243147 | GEO

The CIC::DUX4 oncoprotein maintains DNA integrity through direct regulation of the catalytic subunit of DNA polymerase epsilon (POLE).

Project description:The CIC::DUX4 oncoprotein maintains DNA integrity through direct regulation of the catalytic subunit of DNA polymerase epsilon (POLE).

| PRJNA1172903 | ENA

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