TERT promoter mutations are highly prevalent in advanced thyroid cancers, particularly those harboring BRAF or RAS mutations, whereas PTCs with BRAF or RAS mutations are most often TERT promoter wild type. Acquisition of a TERT promoter mutation could extend survival of BRAF- or RAS-driven clones and enable accumulation of additional genetic defects leading to disease progression.

The BRAF T1799A mutation is the most common genetic alteration in papillary thyroid carcinomas (PTC). It is also found in a subset of papillary microcarcinomas, consistent with a role in tumor initiation. PTCs with BRAF T1799A are often invasive and present at a more advanced stage. BRAF T1799A is found with high prevalence in tall-cell variant PTCs and in poorly differentiated and undifferentiated carcinomas arising from PTCs. To explore the role of BRAF V600E in thyroid cancer pathogenesis, we targeted its expression to thyroid cells of transgenic FVB/N mice with a bovine thyroglobulin promoter. Two Tg-BRAF V600E lines (Tg-BRAF2 and Tg-BRAF3) were propagated for detailed analysis. Tg-BRAF2 and Tg-BRAF3 mice had increased thyroid-stimulating hormone levels (>7-and f2-fold, respectively). This likely resulted from decreased expression of thyroid peroxidase, sodium iodine symporter, and thyroglobulin. All lines seemed to successfully compensate for thyroid dysfunction, as serum thyroxine/triiodothyronine and somatic growth were normal. Thyroid glands of transgenic mice were markedly enlarged by 5 weeks of age. In Tg-BRAF2 mice, PTCs were present at 12 and 22 weeks in 14 of 15 and 13 of 14 animals, respectively, with 83% exhibiting tallcell features, 83% areas of invasion, and 48% foci of poorly differentiated carcinoma. Tg-BRAF3 mice also developed PTCs, albeit with lower prevalence (3 of 12 and 4 of 9 at 12 and 22 weeks, respectively). Tg-BRAF2 mice had a 30% decrease in survival at 5 months. In summary, thyroid-specific expression of BRAF V600E induces goiter and invasive PTC, which transitions to poorly differentiated carcinomas. This closely recapitulates the phenotype of BRAF-positive PTCs in humans and supports a key role for this oncogene in its pathogenesis. (Cancer Res 2005; 65(10): 4238-45)

Cockayne syndrome (CS) is a genetic disorder characterized by developmental abnormalities and photodermatosis resulting from the lack of transcription-coupled nucleotide excision repair, which is responsible for the removal of photodamage from actively transcribed genes. To date, all identified causative mutations for CS have been in the two known CS-associated genes, ERCC8 (CSA) and ERCC6 (CSB). For the rare combined xeroderma pigmentosum (XP) and CS phenotype, all identified mutations are in three of the XP-associated genes, ERCC3 (XPB), ERCC2 (XPD), and ERCC5 (XPG). In a previous report, we identified several CS cases who did not have mutations in any of these genes. In this paper, we describe three CS individuals deficient in ERCC1 or ERCC4 (XPF). Remarkably, one of these individuals with XP complementation group F (XP-F) had clinical features of three different DNA-repair disorders--CS, XP, and Fanconi anemia (FA). Our results, together with those from Bogliolo et al., who describe XPF alterations resulting in FA alone, indicate a multifunctional role for XPF.

Highlights d RNAPII RPB1-K1268 ubiquitination is essential for transcription recovery and DNA repair d Sequential ubiquitination of RNAPII and UVSSA coordinates the recruitment of TFIIH d Strand-specific ChIPseq enables mapping of RNAPII and reveals genome-wide repair kinetics d RNAPII ubiquitination protects against neurodegeneration phenotype in Cockayne syndrome

(1) Mature miRNAs, ranging from 18 to 25 nucleotides in length, processed by two-step cleavage involving Drosha and Dicer are thought to negatively regulate messenger RNA (mRNA). The mature miRNA binds to target mRNA and induces its cleavage or translational repression depending on the degree of complementarity.(2) Although hundreds of miRNAs have been already cloned, only a small number of them have been characterized.Recently, several miRNAs have been reported to be involved in cell proliferation or apoptosis in various types of cancers. (3,4) MiR-15a and miR-16 induce apoptosis by targeting BCL2, and these miRNAs are frequently deleted or underexpressed in chronic lymphocytic leukemia.(5) Let-7 expression is reduced in lung cancer with poor prognosis, (6) and inversely correlates with expression of RAS protein, suggesting a possible mechanism for cancer cell proliferation.(7) Compared to these underexpressed miRNAs, miR-21 has an antiapoptotic function and is overexpressed in glioblastoma. Knockdown of miR-21 in glioblastoma cells induced caspase activation, resulting in apoptotic cell death.(8) Thus, miRNAs can act as both tumor suppressor and oncogene.The miR-17-92 cluster, composed of seven miRNAs (miR-17-5p, miR-17-3p, miR-18a, miR-19a, miR-20a, miR-19b, and miR-92-1) and located in intron 3 of the C13orf25 gene, is overexpressed in lung cancer and B-cell lymphoma.(9,10) Enforced expression of truncated clusters comprising miR-17-5p~19b (miR-17-19b), the vertebrate-specific portion of the miR-17-92 cluster, accelerated tumor development in a mouse B-cell lymphoma model, suggesting oncogenic function of miR-17-19b. On the other hand, O'Donnell et al. have reported that expression of oncogenic E2F1 is negatively regulated by miR-17-5p and miR-20a, members of the cluster, implying that they act as a tumor suppressors.(11) Thus, the function of the cluster is still controversial.In thyroid cancer, overexpression of several miRNAs has been reported. He et al. have reported that three miRNAs (miR-221, miR-222, and miR-146) are overexpressed in papillary thyroid carcinomas (PTC) and regulate KIT expression.(12) Another group has also shown that miR-221, miR-222 and miR-181b are overexpressed in PTC, and inhibition of miR-221 by antisense oligonucleotides led to attenuation of cell growth.(13) In follicular thyroid cancers (FTC), miR-197 and miR-346 are significantly overexpressed. (14) In vitro overexpression of either miRNA induced cell proliferation, whereas inhibition led to growth arrest. Very recently, Visone et al. have reported that significant decrease in miR-30d, miR-125b, miR-26a, and miR-30a-5p was detected in human anaplastic thyroid cancers (ACT). (15) ATC are highly aggressive and fatal tumors with less than 8 months of mean survival after diagnosis.(16) Various treatment patterns including radiation and chemotherapy have been tried in ATC, but they are mostly unsuccessful.(17) Therefore, the identification of miRNAs involved in proliferation or apoptosis in ATC cells has important therapeutic imp...