Insights into the Initiation of Eukaryotic DNA Replication

Bruck, Irina; Pérez-Arnaiz, Patricia; Colbert, Max K; Kaplan, Daniel L.

doi:10.1080/19491034.2015.1115938

Cited by 16 publications

(10 citation statements)

References 68 publications

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“…Further, we attempted to describe the potential functions and mechanisms involving TICRR in PRCC. Based on results from previous studies ( Bruck and Kaplan, 2015 ; Bruck et al, 2015 ), TICRR coordinates the assembly and activation of the eukaryotic replication fork helicase, which further unwinds double-stranded DNA and initiates DNA replication. In our study, based on functional annotation of TICRR -associated DEGs, epithelial cell differentiation and urogenital system development were closely associated with TICRR expression.…”

Section: Discussionmentioning

confidence: 99%

Increased Expression of TICRR Predicts Poor Clinical Outcomes: A Potential Therapeutic Target for Papillary Renal Cell Carcinoma

Xia

Lin

et al. 2021

Front. Genet.

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Background: Papillary renal cell carcinoma (PRCC), although the second-most common type of renal cell carcinoma, still lacks specific biomarkers for diagnosis, treatment, and prognosis. TopBP1-interacting checkpoint and replication regulator (TICRR) is a DNA replication initiation regulator upregulated in various cancers. We aimed to evaluate the role of TICRR in PRCC tumorigenesis and prognosis.Methods: Based on the Kidney Renal Papillary cell carcinoma Project (KIRP) on The Cancer Genome Atlas (TCGA) database, we determined the expression of TICRR using the Wilcoxon rank sum test. The biological functions of TICRR were evaluated using the Metascape database and Gene Set Enrichment Analysis (GSEA). The association between TICRR and immune cell infiltration was investigated by single sample GSEA. Logistic analysis was applied to study the correlation between TICRR expression and clinicopathological characteristics. Finally, Cox regression analysis, Kaplan–Meier analysis, and nomograms were used to determine the predictive value of TICRR on clinical outcomes in PRCC patients.Results:TICRR expression was significantly elevated in PRCC tumors (P < 0.001). Functional annotation indicated enrichment with negative regulation of cell division, cell cycle, and corresponding pathways in the high TICRR expression phenotype. High TICRR expression in PRCC was associated with female sex, younger age, and worse clinical stages. Cox regression analysis revealed that TICRR was a risk factor for overall survival [hazard ratio (HR): 2.80, P = 0.002], progression-free interval (HR: 2.86, P < 0.001), and disease-specific survival (HR: 7.03, P < 0.001), especially in patients with male sex, age below 60 years, clinical stages II–IV and clinical T stage T1–T2.Conclusion: Increased TICRR expression in PRCC might play a role in tumorigenesis by regulating the cell cycle and has prognostic value for clinical outcomes.

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Section: Discussionmentioning

confidence: 99%

Increased Expression of TICRR Predicts Poor Clinical Outcomes: A Potential Therapeutic Target for Papillary Renal Cell Carcinoma

Xia

Lin

et al. 2021

Front. Genet.

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“…Indeed, previous studies have revealed that high expression of initiation factors could promote dormant origins fire early, which can shorten replication timing and accelerate cell proliferation (4–6). Among the identified replication initiation factors, TICRR (also known as Treslin in vertebrate and sld3 in yeast) is likely a hub one (7), as this protein mediates not only the assembly of CMG (CDC45-MCM2-7-GINS) helicase complex by recruiting CDC45 and GINS (3, 8–10), but also the activation of the complex via stimulating MCM2 phosphorylation (11). Recent studies revealed that TICRR/Treslin determined S-phase progression from expression level to epigenetic control (12–14).…”

Section: Introductionmentioning

confidence: 99%

TICRR Contributes to Tumorigenesis Through Accelerating DNA Replication in Cancers

et al. 2019

Front. Oncol.

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DNA replication is precisely regulated in cells and its dysregulation can trigger tumorigenesis. Here we identified that the TOPBP1 interacting checkpoint and replication regulator ( TICRR ) mRNA level was universally and highly expressed in 15 solid cancer types. Depletion of TICRR significantly inhibited tumor cell growth, colony formation and migration in vitro , and strikingly inhibited tumor growth in the xenograft model. We reveal that knockdown of TICRR inhibited not only the initiation but also the fork progression of DNA replication. Suppression of DNA synthesis by TICRR silencing caused DNA damage accumulation, subsequently activated the ATM/CHK2 dependent p53 signaling, and finally induced cell cycle arrest and apoptosis at least in p53-wild cancer cells. Further, we show that a higher TICRR level was associated with poorer overall survival (OS) and disease free survival (DFS) in multiple cancer types. In conclusion, our study shows that TICRR is involved in tumorigenesis by regulating DNA replication, acting as a common biomarker for cancer prognosis and could be a promising target for drug-development and cancer treatment.

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“…The genomic region Gain 2 from chromosome 8 also contains additional genes important for cancer development. Thus, the overexpression of MCM4 gene was detected in laryngeal squamous cell carcinoma and this gene was also implicated in other cancers because it codes for an important component of the DNA replication machinery [ 43 , 44 ]. Inside the genomic region Gain 2 a continuous segment, named Gain 3, was obverved, which showed an even a higher level of association and contained the SNAI2 gene.…”

Section: Discussionmentioning

confidence: 99%

Identification of genomic copy number variations associated with specific clinical features of head and neck cancer

et al. 2018

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BackgroundCopy number variations (CNSs) of large genomic regions are an important mechanism implicated in the development of head and neck cancer, however, for most changes their exact role is not well understood. The aim of this study was to find possible associations between gains/losses of genomic regions and clinically distinct subgroups of head and neck cancer patients.ResultsArray comparative genomic hybridization (aCGH) analysis was performed on DNA samples in 64 patients with cancer in oral cavity, oropharynx or hypopharynx. Overlapping genomic regions created from gains and losses were used for statistical analysis. Following regions were overrepresented: in tumors with stage I or II a gain of 2.98 Mb on 6p21.2-p11 and a gain of 7.4 Mb on 8q11.1-q11.23; in tumors with grade I histology a gain of 1.1 Mb on 8q24.13, a loss of a large part of p arm of chromosome 3, a loss of a 1.24 Mb on 6q14.3, and a loss of terminal 32 Mb region of 8p23.3; in cases with affected lymph nodes a gain of 0.75 Mb on 3q24, and a gain of 0.9 Mb on 3q26.32-q26.33; in cases with unaffected lymph nodes a gain of 1.1 Mb on 8q23.3, in patients not treated with surgery a gain of 12.2 Mb on 7q21.3-q22.3 and a gain of 0.33 Mb on 20q11.22.ConclusionsOur study identified several genomic regions of interest which appear to be associated with various clinically distinct subgroups of head and neck cancer. They represent a potentially important source of biomarkers useful for the clinical management of head and neck cancer. In particular, the PIK3CA and AGTR1 genes could be singled out to predict the lymph node involvement.

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Insights into the Initiation of Eukaryotic DNA Replication

Cited by 16 publications

References 68 publications

Increased Expression of TICRR Predicts Poor Clinical Outcomes: A Potential Therapeutic Target for Papillary Renal Cell Carcinoma

Increased Expression of TICRR Predicts Poor Clinical Outcomes: A Potential Therapeutic Target for Papillary Renal Cell Carcinoma

TICRR Contributes to Tumorigenesis Through Accelerating DNA Replication in Cancers

Identification of genomic copy number variations associated with specific clinical features of head and neck cancer

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