Telomeres, the DNA-protein complexes located at end of linear eukaryotic chromosomes, are essential for chromosome stability. Until now, telomeres have been considered to be transcriptionally silent. We demonstrate that mammalian transcribed into telomeric repeat–containing RNA (TERRA). TERRA molecules heterogeneous in length, from several subtelomeric loci toward ends, and localize telomeres. also show suppressors with morphogenetic defects genitalia (SMG) proteins, which effectors...

Abstract A fraction of cancer cells maintain telomeres through the telomerase-independent, ‘Alternative Lengthening Telomeres’ (ALT) pathway. ALT relies on homologous recombination (HR) between telomeric sequences; yet, what makes recombinogenic remains unclear. Here we show that RNA endonuclease RNaseH1 regulates levels RNA–DNA hybrids DNA and long noncoding TERRA, is a key mediator telomere maintenance in cells. associated to specifically its depletion led hybrid accumulation, exposure...

Abstract Telomerase negative immortal cancer cells elongate telomeres through the Alternative Lengthening of Telomeres (ALT) pathway. While sustained telomeric replicative stress is required to maintain ALT, it might also lead cell death when excessive. Here, we show that ATPase/translocase activity FANCM keeps in check specifically ALT cells. When depleted cells, become dysfunctional, and stop proliferating die. depletion increases ALT-associated marks de novo synthesis DNA. Depletion BLM...

The longstanding dogma that telomeres, the heterochromatic extremities of linear eukaryotic chromosomes, are transcriptionally silent was overturned by discovery DNA-dependent RNA polymerase II (RNAPII) transcribes telomeric DNA into repeat-containing (TERRA). Here, we show CpG dinucleotide-rich islands, shared among multiple human chromosome ends, promote transcription TERRA molecules. promoters sustain cellular expression reporter genes, located immediately upstream start sites, and bound...

The binding of sequence-specific RNA-interacting proteins, such as the bacteriophage MS2 or PP7 coat to their corresponding target sequences has been extremely useful and widely used visualize single mRNAs in vivo. However, introduction stem-loops into yeast recently shown lead accumulation RNA fragments, suggesting that loops impair mRNA decay. This result was questioned, because fragment occurrence mainly assessed using ensemble methods, cellular localization its implications had not...

Alternative Lengthening of Telomeres (ALT) is a Break-Induced Replication (BIR)-based mechanism elongating telomeres in subset human cancer cells. While the notion that spontaneous DNA damage at required to initiate ALT, molecular triggers this physiological telomere instability are largely unknown. We previously proposed telomeric long noncoding RNA TERRA may represent one such trigger; however, given lack tools suppress transcription cells, our hypothesis remained speculative. have...

Eukaryotic telomeres are transcribed into telomeric repeat-containing RNA (TERRA). Telomeric transcription has been documented in mammals, birds, zebra fish, plants and budding yeast. Here we show that the chromosome ends of Schizosaccharomyces pombe produce distinct species. As with yeast S. contains G-rich TERRA molecules subtelomeric species opposite direction (ARRET). Moreover, fission two novel species: C-rich transcripts (ARIA) complementary to ARRET (αARRET). polymerase II (RNAPII)...

RNA polymerase II transcribes the physical ends of linear eukaryotic chromosomes into a variety long non-coding molecules including telomeric repeat-containing (TERRA). Since TERRA discovery, advances have been made in characterization biogenesis and regulation; on contrary its associated functions remain elusive. Most biological roles so far proposed for are indeed based vitro experiments carried out using short TERRA-like oligonucleotides. In particular, it has suggested that inhibits...

Clericuzio-type poikiloderma with neutropenia (PN) is a rare genodermatosis associated mutations in the C16orf57 gene, which codes for uncharacterized protein hMpn1. We show here that, both fission yeasts and humans, Mpn1 processes spliceosomal U6 small nuclear RNA (snRNA) posttranscriptionally. In Mpn1-deficient cells, molecules carry 3′ end polyuridine tails that are longer than those normal cells lack terminal 2′,3′ cyclic phosphate group. mpn1Δ yeast snRNA U4/U6 di-small complex levels...

A substantial number of human cancers are telomerase-negative and elongate physiologically damaged telomeres through a break-induced replication (BIR)-based mechanism known as alternative lengthening (ALT). We recently demonstrated that inhibiting the transcription telomeric long noncoding RNA TERRA suppresses telomere damage ALT features, indicating is main trigger activity. Here we show experimentally increased not only increases expected, but also causes rapid loss DNA pathway requires...

Patricia L. Abreu1,5, Valentina Riva1,3,5, Luca Zardoni1,4,5 and Claus M. Azzalin1,2 1GIMM - Gulbenkian Institute for Molecular Medicine, 1649-035 Lisbon, Portugal 2Faculty of University 1649-028 Correspondence: claus.azzalin{at}gimm.pt ↵3 Current address: Science Technology Austria, Am Campus 1, 3400 Klosterneuburg, Austria. ↵4 Istituto di Genetica Molecolare Luigi Cavalli-Sforza, CNR, 27100 Pavia, Italy. ↵5 These authors contributed equally to this work.

Short blocks of telomeric-like DNA (Interstitial Telomeric Sequences, ITSs) are found far from chromosome ends. We addressed the question as to how such sequences arise by comparing loci 10 human ITSs with their genomic orthologs in 12 primate species. The did not derive expansion pre-existing TTAGGG units, described for other microsatellites, but appeared suddenly during evolution. Nine insertion events were dated along evolutionary tree, dates ranging between 40 and 6 million years ago....

The Smg proteins Smg5, Smg6 and Smg7 are involved in nonsense-mediated RNA decay (NMD) metazoans, but no orthologs have been found the budding yeast Saccharomyces cerevisiae. Sequence alignments reveal that Ebs1p is similar structure to human Smg5-7, with highest homology Smg7. We demonstrate here NMD behaves similarly proteins. Indeed, both loss overexpression of results stabilization targets. However, Ebs1-loss or Smg7-depletion cells only partially disrupts latter, compensated for by...