PARP1 Deficiency Reduces Tumour Growth by Decreasing E2F1 Hyperactivation: A Novel Mechanism Beyond PARP Enzymatic Inhibition in the Treatment of Cancer

In recent years, poly (ADP-ribose) polymerase (PARP) inhibitors have heen evaluated for treating homologous recombination-deficient tumors, taking advantage of synthetic lethality. However, increasing evidence indicates that PARP proteins exert several cellular functions unrelated with their role on DNA repair, including function as a co-activators of transcription through protein-protein interaction with E2F1. Since the RB/E2F1 pathway is among the most frequently mutated in many tumours types, we investigated whether the absence of PARP activity could counteract the consequences of E2F1 hyperactivation. Our results demonstrate that genetic ablation of Parp1 extends the survival of Rb-null embryos, while genetic inactivation of Parp1 results in reduced development of pRb-dependent tumors. Our results demonstrate that PARP1 plays a key role as a transcriptional co-activator of the transcription factor E2F1, an important component of the cell cycle regulation. Furthermore, impairment of PARP results in a reduction of tumor growth, that is not depending of the activity of PARP on DNA repair. Considering that most oncogenic processes are associated with cell cycle deregulation, the disruption of this PARP1-E2F1 interaction could provide a new therapeutic target of great interest and a wide spectrum of indications.

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PARP1 Deficiency Reduces Tumour Growth by Decreasing E2F1 Hyperactivation: A Novel Mechanism in the Treatment of Cancer

Cancers ◽

10.3390/cancers12102907 ◽

2020 ◽

Vol 12 (10) ◽

pp. 2907

Author(s):

Pablo Iglesias ◽

Marcos Seoane ◽

Irene Golán ◽

Isabel Castro-Piedras ◽

Máximo Fraga ◽

...

Keyword(s):

Cell Cycle ◽

Synthetic Lethality ◽

Wide Spectrum ◽

Parp Inhibitors ◽

Cellular Functions ◽

Genetic Ablation ◽

Protein Protein Interaction ◽

Parp Activity ◽

Cell Cycle Deregulation ◽

Cycle Regulation

In recent years, poly (ADP-ribose) polymerase (PARP) inhibitors have been evaluated for treating homologous recombination-deficient tumours, taking advantage of synthetic lethality. However, increasing evidence indicates that PARP1 exert several cellular functions unrelated with their role on DNA repair, including function as a co-activator of transcription through protein-protein interaction with E2F1. Since the RB/E2F1 pathway is among the most frequently mutated in many tumour types, we investigated whether the absence of PARP activity could counteract the consequences of E2F1 hyperactivation. Our results demonstrate that genetic ablation of Parp1 extends the survival of Rb-null embryos, while genetic inactivation of Parp1 results in reduced development of pRb-dependent tumours. Our results demonstrate that PARP1 plays a key role as a transcriptional co-activator of the transcription factor E2F1, an important component of the cell cycle regulation. Considering that most oncogenic processes are associated with cell cycle deregulation, the disruption of this PARP1-E2F1 interaction could provide a new therapeutic target of great interest and a wide spectrum of indications.

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Yeast Sphingolipid Phospholipase Gene ISC1 Regulates the Spindle Checkpoint by a CDC55-Dependent Mechanism

Molecular and Cellular Biology ◽

10.1128/mcb.00340-19 ◽

2020 ◽

Vol 40 (12) ◽

Author(s):

Nabil Matmati ◽

Bachar H. Hassan ◽

Jihui Ren ◽

Ashraf A. Shamssedine ◽

Eunmi Jeong ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Regulation ◽

Spindle Assembly Checkpoint ◽

Synthetic Lethality ◽

Spindle Checkpoint ◽

Cellular Functions ◽

Spindle Elongation ◽

Synthetically Lethal ◽

Cycle Regulation ◽

Checkpoint Genes

ABSTRACT Defects in the spindle assembly checkpoint (SAC) can lead to aneuploidy and cancer. Sphingolipids have important roles in many cellular functions, including cell cycle regulation and apoptosis. However, the specific mechanisms and functions of sphingolipids in cell cycle regulation have not been elucidated. Using analysis of concordance for synthetic lethality for the yeast sphingolipid phospholipase ISC1, we identified two groups of genes. The first comprises genes involved in chromosome segregation and stability (CSM3, CTF4, YKE2, DCC1, and GIM4) as synthetically lethal with ISC1. The second group, to which ISC1 belongs, comprises genes involved in the spindle checkpoint (BUB1, MAD1, BIM1, and KAR3), and they all share the same synthetic lethality with the first group. We demonstrate that spindle checkpoint genes act upstream of Isc1, and their deletion phenocopies that of ISC1. Reciprocally, ISC1 deletion mutants were sensitive to benomyl, indicating a SAC defect. Similar to BUB1 deletion, ISC1 deletion prevents spindle elongation in hydroxyurea-treated cells. Mechanistically, PP2A-Cdc55 ceramide-activated phosphatase was found to act downstream of Isc1, thus coupling the spindle checkpoint genes and Isc1 to CDC55-mediated nuclear functions.

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Genetic variants and cognitive functions in patients with brain tumors

Neuro-Oncology ◽

10.1093/neuonc/noz094 ◽

2019 ◽

Vol 21 (10) ◽

pp. 1297-1309 ◽

Cited By ~ 5

Author(s):

Denise D Correa ◽

Jaya Satagopan ◽

Axel Martin ◽

Erica Braun ◽

Maria Kryza-Lacombe ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Cycle ◽

Dna Repair ◽

Brain Tumor ◽

Brain Tumors ◽

Cell Cycle Regulation ◽

Cognitive Outcome ◽

Cholesterol Transport ◽

Tumor Patients ◽

Cycle Regulation

AbstractBackgroundPatients with brain tumors treated with radiotherapy (RT) and chemotherapy (CT) often experience cognitive dysfunction. We reported that single nucleotide polymorphisms (SNPs) in the APOE, COMT, and BDNF genes may influence cognition in brain tumor patients. In this study, we assessed whether genes associated with late-onset Alzheimer’s disease (LOAD), inflammation, cholesterol transport, dopamine and myelin regulation, and DNA repair may influence cognitive outcome in this population.MethodsOne hundred and fifty brain tumor patients treated with RT ± CT or CT alone completed a neurocognitive assessment and provided a blood sample for genotyping. We genotyped genes/SNPs in these pathways: (i) LOAD risk/inflammation/cholesterol transport, (ii) dopamine regulation, (iii) myelin regulation, (iv) DNA repair, (v) blood–brain barrier disruption, (vi) cell cycle regulation, and (vii) response to oxidative stress. White matter (WM) abnormalities were rated on brain MRIs.ResultsMultivariable linear regression analysis with Bayesian shrinkage estimation of SNP effects, adjusting for relevant demographic, disease, and treatment variables, indicated strong associations (posterior association summary [PAS] ≥ 0.95) among tests of attention, executive functions, and memory and 33 SNPs in genes involved in: LOAD/inflammation/cholesterol transport (eg, PDE7A, IL-6), dopamine regulation (eg, DRD1, COMT), myelin repair (eg, TCF4), DNA repair (eg, RAD51), cell cycle regulation (eg, SESN1), and response to oxidative stress (eg, GSTP1). The SNPs were not significantly associated with WM abnormalities.ConclusionThis novel study suggests that polymorphisms in genes involved in aging and inflammation, dopamine, myelin and cell cycle regulation, and DNA repair and response to oxidative stress may be associated with cognitive outcome in patients with brain tumors.

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Targeting Non-Oncogene Addiction for Cancer Therapy

Biomolecules ◽

10.3390/biom11020129 ◽

2021 ◽

Vol 11 (2) ◽

pp. 129

Author(s):

Hae Ryung Chang ◽

Eunyoung Jung ◽

Soobin Cho ◽

Young-Jun Jeon ◽

Yonghwan Kim

Keyword(s):

Cell Cycle ◽

Dna Replication ◽

Cancer Therapy ◽

Cell Cycle Regulation ◽

Synthetic Lethality ◽

Current Knowledge ◽

Cancer Therapies ◽

Oncogene Addiction ◽

Clinical Biomarkers ◽

Cycle Regulation

While Next-Generation Sequencing (NGS) and technological advances have been useful in identifying genetic profiles of tumorigenesis, novel target proteins and various clinical biomarkers, cancer continues to be a major global health threat. DNA replication, DNA damage response (DDR) and repair, and cell cycle regulation continue to be essential systems in targeted cancer therapies. Although many genes involved in DDR are known to be tumor suppressor genes, cancer cells are often dependent and addicted to these genes, making them excellent therapeutic targets. In this review, genes implicated in DNA replication, DDR, DNA repair, cell cycle regulation are discussed with reference to peptide or small molecule inhibitors which may prove therapeutic in cancer patients. Additionally, the potential of utilizing novel synthetic lethal genes in these pathways is examined, providing possible new targets for future therapeutics. Specifically, we evaluate the potential of TONSL as a novel gene for targeted therapy. Although it is a scaffold protein with no known enzymatic activity, the strategy used for developing PCNA inhibitors can also be utilized to target TONSL. This review summarizes current knowledge on non-oncogene addiction, and the utilization of synthetic lethality for developing novel inhibitors targeting non-oncogenic addiction for cancer therapy.

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Focus-ING on DNA Integrity: Implication of ING Proteins in Cell Cycle Regulation and DNA Repair Modulation

Cancers ◽

10.3390/cancers12010058 ◽

2019 ◽

Vol 12 (1) ◽

pp. 58

Author(s):

Jérôme Archambeau ◽

Alice Blondel ◽

Rémy Pedeux

Keyword(s):

Cell Cycle ◽

Dna Repair ◽

Chromatin Remodeling ◽

Tumor Suppressor Genes ◽

Cell Cycle Regulation ◽

Genomic Stability ◽

Dna Integrity ◽

Damage Response ◽

The Stability ◽

Cycle Regulation

The ING family of tumor suppressor genes is composed of five members (ING1-5) involved in cell cycle regulation, DNA damage response, apoptosis and senescence. All ING proteins belong to various HAT or HDAC complexes and participate in chromatin remodeling that is essential for genomic stability and signaling pathways. The gatekeeper functions of the INGs are well described by their role in the negative regulation of the cell cycle, notably by modulating the stability of p53 or the p300 HAT activity. However, the caretaker functions are described only for ING1, ING2 and ING3. This is due to their involvement in DNA repair such as ING1 that participates not only in NERs after UV-induced damage, but also in DSB repair in which ING2 and ING3 are required for accumulation of ATM, 53BP1 and BRCA1 near the lesion and for the subsequent repair. This review summarizes evidence of the critical roles of ING proteins in cell cycle regulation and DNA repair to maintain genomic stability.

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Frequency and prognostic value of mutations associated with the homologous recombination DNA repair pathway in a large pan cancer cohort

Scientific Reports ◽

10.1038/s41598-020-76975-6 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Daniel R. Principe ◽

Matthew Narbutis ◽

Regina Koch ◽

Ajay Rana

Keyword(s):

Dna Repair ◽

Homologous Recombination ◽

Synthetic Lethality ◽

Parp Inhibitors ◽

The Cancer Genome Atlas ◽

Parp Inhibition ◽

Repair Pathway ◽

Wide Range ◽

Recombination Pathway ◽

Pan Cancer

AbstractPARP inhibitors have shown remarkable efficacy in the clinical management of several BRCA-mutated tumors. This approach is based on the long-standing hypothesis that PARP inhibition will impair the repair of single stranded breaks, causing synthetic lethality in tumors with loss of high-fidelity double-strand break homologous recombination. While this is now well accepted and has been the basis of several successful clinical trials, emerging evidence strongly suggests that mutation to several additional genes involved in homologous recombination may also have predictive value for PARP inhibitors. While this notion is supported by early clinical evidence, the mutation frequencies of these and other functionally related genes are largely unknown, particularly in cancers not classically associated with homologous recombination deficiency. We therefore evaluated the mutation status of 22 genes associated with the homologous recombination DNA repair pathway or PARP inhibitor sensitivity, first in a pan-cancer cohort of 55,586 patients, followed by a more focused analysis in The Cancer Genome Atlas cohort of 12,153 patients. In both groups we observed high rates of mutations in a variety of HR-associated genes largely unexplored in the setting of PARP inhibition, many of which were associated also with poor clinical outcomes. We then extended our study to determine which mutations have a known oncogenic role, as well as similar to known oncogenic mutations that may have a similar phenotype. Finally, we explored the individual cancer histologies in which these genomic alterations are most frequent. We concluded that the rates of deleterious mutations affecting genes associated with the homologous recombination pathway may be underrepresented in a wide range of human cancers, and several of these genes warrant further and more focused investigation, particularly in the setting of PARP inhibition and HR deficiency.

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