Modulation of Telomeres in Alternative Lengthening of Telomeres Type I Like Human Cells by the Expression of Werner Protein and Telomerase

Siddiqa, Aisha; Cavazos, David; Chavez, Jeffery B.; Long, Linda M; Marciniak, Robert A.

doi:10.1155/2012/806382

Cited by 9 publications

(10 citation statements)

References 47 publications

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“…Cancer cells activate mechanisms to maintain telomere length and enhance proliferation. While most cancers reactivate telomerase, a significant proportion initiate the ALT-pathway [100], and links of ALT activation to tumors with complex karyotypes have been reported [101-103]. A study by Reddel and colleagues [101] identifies a correlation between patient age and ALT activation, which is seen mostly in young individuals [101].…”

Section: Discussionmentioning

confidence: 99%

The role of post-translational modifications in fine-tuning BLM helicase function during DNA repair

Böhm

Bernstein

2014

DNA Repair

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RecQ-like helicases are a highly conserved family of proteins which are critical for preserving genome integrity. Genome instability is considered a hallmark of cancer and mutations within three of the five human RECQ genes cause hereditary syndromes that are associated with cancer predisposition. The human RecQ-like helicase BLM has a central role in DNA damage signaling, repair, replication, and telomere maintenance. BLM and its budding yeast orthologue Sgs1 unwind double-stranded DNA intermediates. Intriguingly, BLM functions in both a pro- and anti-recombinogenic manner upon replicative damage, acting on similar substrates. Thus, BLM activity must be intricately controlled to prevent illegitimate recombination events that could have detrimental effects on genome integrity. In recent years it has become evident that post-translational modifications (PTMs) of BLM allow a fine-tuning of its function. To date, BLM phosphorylation, ubiquitination, and SUMOylation have been identified, in turn regulating its subcellular localization, protein-protein interactions, and protein stability. In this review, we will discuss the cellular context of when and how these different modifications of BLM occur. We will reflect on the current model of how PTMs control BLM function during DNA damage repair and compare this to what is known about post-translational regulation of the budding yeast orthologue Sgs1. Finally, we will provide an outlook towards future research, in particular to dissect the cross-talk between the individual PTMs on BLM.

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Section: Discussionmentioning

confidence: 99%

The role of post-translational modifications in fine-tuning BLM helicase function during DNA repair

Böhm

Bernstein

2014

DNA Repair

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“…OSCC cells were cultured on coverslips (1 × 10 5 ), fixed with 4% paraformaldehyde and stained as previously described [21,22] with antibodies to total ALK antibody (1:100; #ABN263 EMD Millipore, Billerica, MA) and p-ALK (1:100); #MBS855239; MyBio-Source; San Diego, CA) and anti-rabbit Alexa Flour 488 secondary antibody (1:100; #A-11008, ThermoFisher, Waltham, MA) and DAPI 1 μg/ml (ThermoFisher) as a nuclear stain. Images were acquired with a Nikon TE2000U microscope using a 40×/1.3NA objective lens and processed for illustration purposes with NIS-Elements imaging software (Nikon, Brighton, MI).…”

Section: Methodsmentioning

confidence: 99%

Co-targeting ALK and EGFR parallel signaling in oral squamous cell carcinoma

et al. 2016

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Squamous cell carcinoma (SCC) comprises 90% of all head and neck cancers and has a poor survival rate due to late-stage disease that is refractive to traditional therapies. Epidermal growth factor receptor (EGFR) is over-expressed in greater than 80% of head and neck SCC (HNSCC). However, EGFR targeted therapies yielded little to no efficacy in clinical trials. This study investigated the efficacy of co-targeting EGFR and the anaplastic lymphoma kinase (ALK) whose promoter is hypomethylated in late-stage oral SCC (OSCC). We observed increased ALK activity in late-stage human OSCC tumors and invasive OSCC cell lines. We also found that while ALK inhibition alone had little effect on proliferation, co-targeting ALK and EGFR significantly reduced OSCC cell proliferation in vitro. Further analysis showed significant efficacy of combined treatment in HSC3-derived xenografts resulting in a 30% decrease in tumor volumes by 14 days (p < 0.001). Western blot analysis showed that co-targeting ALK and EGFR significantly reduced EGFR phosphorylation (Y1148) in HSC3 cells but not Cal27 cells. ALK and EGFR downstream signaling interactions are also demonstrated by Western blot analysis in which lone EGFR and ALK inhibitors attenuated AKT activity whereas co-targeting ALK and EGFR completely abolished AKT activation. No effects were observed on ERK1/2 activation. STAT3 activity was significantly induced by lone ALK inhibition in HSC3 cells and to a lower extent in Cal27 cells. Together, these data illustrate that ALK inhibitors enhance anti-tumor activity of EGFR inhibitors in susceptible tumors that display increased ALK expression, most likely through abolition of AKT activation.

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“…3,4 It is possible that these tumors do not activate a telomere maintenance mechanism similar to low-grade astrocytomas, 16,17 or that their telomere maintenance mechanism remains undescribed. [18][19][20] Another possibility is that non-defined telomere maintenance mechanism tumors are comprised of telomerase and alternative lengthening of telomere-positive tumors, but complications in assaying telomerase activity and measuring the hallmarks of the alternative lengthening of telomeres mechanism lead to falsenegative results. Many glioblastomas contain a considerable proportion of non-neoplastic cells such as macrophages/microglia (tumor-associated macrophages) that can comprise over 70% of the tumor.…”

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confidence: 99%

Telomere profiles and tumor-associated macrophages with different immune signatures affect prognosis in glioblastoma

et al. 2016

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Telomere maintenance is a hallmark of cancer and likely to be targeted in future treatments. In glioblastoma established methods of identifying telomerase and alternative lengthening of telomeres leave a significant proportion of tumors with no defined telomere maintenance mechanism. This study investigated the composition of these tumors using RNA-Seq. Glioblastomas with an indeterminate telomere maintenance mechanism had an increased immune signature compared with alternative lengthening of telomeres and telomerase-positive tumors. Immunohistochemistry for CD163 confirmed that the majority (80%) of tumors with an indeterminate telomere maintenance mechanism had a high presence of tumor-associated macrophages. The RNA-Seq and immunostaining data separated tumors with no defined telomere maintenance mechanism into three subgroups: alternative lengthening of telomeres like tumors with a high presence of tumor-associated macrophages and telomerase like tumors with a high presence of tumor-associated macrophages. The third subgroup had no increase in tumor-associated macrophages and may represent a distinct category. The presence of tumorassociated macrophages conferred a worse prognosis with reduced patient survival times (alternative lengthening of telomeres with and without macrophages P = 0.0004, and telomerase with and without macrophages P = 0.013). The immune signatures obtained from RNA-Seq were significantly different between telomere maintenance mechanisms. Alternative lengthening of telomeres like tumors with macrophages had increased expression of interferon-induced proteins with tetratricopeptide repeats (IFIT1-3). Telomerase-positive tumors with macrophages had increased expression of macrophage receptor with collagenous structure (MARCO), CXCL12 and sushi-repeat containing protein x-linked 2 (SRPX2). Telomerase-positive tumors with macrophages were also associated with a reduced frequency of total/near total resections (44% vs 476% for all other subtypes, P = 0.014). In summary, different immune signatures are found among telomere maintenance mechanism-based subgroups in glioblastoma. The reduced extent of surgical resection of telomerase-positive tumors with macrophages suggests that some tumor-associated macrophages are more unfavorable.

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Modulation of Telomeres in Alternative Lengthening of Telomeres Type I Like Human Cells by the Expression of Werner Protein and Telomerase

Cited by 9 publications

References 47 publications

The role of post-translational modifications in fine-tuning BLM helicase function during DNA repair

The role of post-translational modifications in fine-tuning BLM helicase function during DNA repair

Co-targeting ALK and EGFR parallel signaling in oral squamous cell carcinoma

Telomere profiles and tumor-associated macrophages with different immune signatures affect prognosis in glioblastoma

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