Translating the telomeres.

Telomeres are transcribed into long noncoding telomeric repeat-containing RNA (TERRA). Or so we thought. Recently, Al-Turki and Griffith provided evidence that TERRA can code for valine-arginine (VR) or glycine-leucine (GL) dipeptide repeat proteins by undergoing repeat-associated non-ATG (RAN) translation.

OGG1 and MUTYH repair activities promote telomeric 8-oxoguanine induced cellular senescence.

Telomeres are prone to formation of the common oxidative lesion 8-oxoguanine (8oxoG), and the acute production of 8oxoG damage at telomeres is sufficient to drive rapid cellular senescence. OGG1 and MUTYH glycosylases initiate base excision repair (BER) at 8oxoG sites to remove the lesion or prevent mutation. Here, we show OGG1 loss or inhibition, or MUTYH loss, partially rescues telomeric 8oxoG-induced senescence, and loss of both glycosylases results in a near complete rescue.

Telomeric 8-oxo-guanine drives rapid premature senescence in the absence of telomere shortening.

Oxidative stress is a primary cause of cellular senescence and contributes to the etiology of numerous human diseases. Oxidative damage to telomeric DNA has been proposed to cause premature senescence by accelerating telomere shortening. Here, we tested this model directly using a precision chemoptogenetic tool to produce the common lesion 8-oxo-guanine (8oxoG) exclusively at telomeres in human fibroblasts and epithelial cells.

Roles for the 8-Oxoguanine DNA Repair System in Protecting Telomeres From Oxidative Stress.

Telomeres are protective nucleoprotein structures that cap linear chromosome ends and safeguard genome stability. Progressive telomere shortening at each somatic cell division eventually leads to critically short and dysfunctional telomeres, which can contribute to either cellular senescence and aging, or tumorigenesis. Human reproductive cells, some stem cells, and most cancer cells, express the enzyme telomerase to restore telomeric DNA.

Designer Fluorescent Adenines Enable Real-Time Monitoring of MUTYH Activity.

The human DNA base excision repair enzyme MUTYH (MutY homolog DNA glycosylase) excises undamaged adenine that has been misincorporated opposite the oxidatively damaged 8-oxoG, preventing transversion mutations and serving as an important defense against the deleterious effects of this damage. Mutations in the gene predispose patients to MUTYH-associated polyposis and colorectal cancer, and MUTYH expression has been documented as a biomarker for pancreatic cancer. Measuring MUTYH activity is therefore critical for evaluating and diagnosing disease states as well as for testing this enzyme as a potential therapeutic target.

Methylation of the Suppressor Gene : Mechanism and Consequences.

Tumor suppressor genes in the locus (, , and ) function as biological barriers to transformation and are the most frequently silenced or deleted genes in human cancers. This gene silencing frequently occurs due to DNA methylation of the promoter regions, although the underlying mechanism is currently unknown. We present evidence that methylation of promoter is associated with DNA damage caused by interference between transcription and replication processes.

RNA Stabilizes Transcription-Dependent Chromatin Loops Induced By Nuclear Hormones.

We show that transcription induced by nuclear receptors for estrogen (E) or retinoic acid (RA) is associated with formation of chromatin loops that juxtapose the 5' end (containing the promoter) with the enhancer and the 3' polyA addition site of the target gene. We find three loop configurations which change as a function of time after induction: 1. RA or E-induced loops which connect the 5' end, the enhancer and the 3' end of the gene, and are stabilized by RNA early after induction; 2.

DNA damage signatures in peripheral blood cells as biomarkers in prodromal huntington disease.

Easily accessible biomarkers in Huntington disease (HD) are actively searched. We investigated telomere length and DNA double-strand breaks (histone variant pγ-H2AX) as predictive disease biomarkers in peripheral blood mononuclear cells (PBMC) from 25 premanifest subjects, 58 HD patients with similar CAG expansion in the huntingtin gene (HTT), and 44 healthy controls (HC). PBMC from the pre-HD and HD groups showed shorter telomeres (p < 0.

Up-regulation of miR-146b and down-regulation of miR-200b contribute to the cytotoxic effect of histone deacetylase inhibitors on ras-transformed thyroid cells.

Context: Histone deacetylase inhibitors (HDACis) are anticancer agents that inhibit tumor cell growth and/or survival. However, their mechanism of action remains largely undefined. Recently, we have demonstrated that HDACis induce apoptosis in a model of rat thyroid cells transformed by the v-ras-Ki oncogene (FRTL-5 v-ras-Ki).