Telomeric Strategies: Means to an End

Jain, Devanshi; Cooper, Julia Promisel

doi:10.1146/annurev-genet-102108-134841

Cited by 185 publications

(177 citation statements)

References 221 publications

(201 reference statements)

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“…In QTIP, the proteins in the different cell populations to be compared are differentially labelled by incubating the cells in medium containing either heavy isotopes ([ 13 C 6 15 N 4 ]Arg (R10) and [ 13 C 6 15 N 2 ]Lys (K8)) or light isotopes (Arg (R0) and Lys (K0)) (Approach A, Fig. 1a).…”

Section: Implementation Of Qtipmentioning

confidence: 99%

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A quantitative telomeric chromatin isolation protocol identifies different telomeric states

et al. 2013

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Telomere composition changes during tumourigenesis, aging and in telomere syndromes in a poorly defined manner. Here we develop a quantitative telomeric chromatin isolation protocol (QTIP) for human cells, in which chromatin is cross-linked, immunopurified and analysed by mass spectrometry. QTIP involves stable isotope labelling by amino acids in cell culture (SILAC) to compare and identify quantitative differences in telomere protein composition of cells from various states. With QTIP, we specifically enrich telomeric DNA and all shelterin components. We validate the method characterizing changes at dysfunctional telomeres, and identify and validate known, as well as novel telomere-associated polypeptides including all THO subunits, SMCHD1 and LRIF1. We apply QTIP to long and short telomeres and detect increased density of SMCHD1 and LRIF1 and increased association of the shelterins TRF1, TIN2, TPP1 and POT1 with long telomeres. Our results validate QTIP to study telomeric states during normal development and in disease.

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Section: Implementation Of Qtipmentioning

confidence: 99%

“…Telomeric DNA consists of simple repetitive DNA sequences (5 0 -TTAGGG-3 0 /5 0 -CCCTAA-3 0 repeats in humans) of several kilobases and terminates with single-stranded (ss) 3 0 overhangs measuring a few hundred nucleotides 6 . Telomeric DNA is assembled with specialized telomere-binding proteins.…”

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confidence: 99%

A quantitative telomeric chromatin isolation protocol identifies different telomeric states

et al. 2013

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“…In contrast, addition of Zscan4 resulted in 8.36-fold, 6.20-fold and 4.37-fold increases in T-SCE frequency in OSKMZ-infected MEFs on days 3, 6 and 9 post-infection ( Figure 4C and 4D), respectively. We also analyzed expression levels of shelterin components and found that Trf2, Pot1b and Rap1, which can inhibit T-SCE after replication [39,40], were repressed when Zscan4 was overexpressed ( Figure 5A). Other shelterin proteins, Trf1, Pot1a, Tpp1 and Tin2, were not repressed ( Figure 5B).…”

Section: Zscan4 Promotes Telomere Elongation During Reprogrammingmentioning

confidence: 99%

Zscan4 promotes genomic stability during reprogramming and dramatically improves the quality of iPS cells as demonstrated by tetraploid complementation

et al. 2012

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Induced pluripotent stem (iPS) cells generated using Yamanaka factors have great potential for use in autologous cell therapy. However, genomic abnormalities exist in human iPS cells, and most mouse iPS cells are not fully pluripotent, as evaluated by the tetraploid complementation assay (TCA); this is most likely associated with the DNA damage response (DDR) occurred in early reprogramming induced by Yamanaka factors. In contrast, nuclear transfer can faithfully reprogram somatic cells into embryonic stem (ES) cells that satisfy the TCA. We thus hypothesized that factors involved in oocyte-induced reprogramming may stabilize the somatic genome during reprogramming, and improve the quality of the resultant iPS cells. To test this hypothesis, we screened for factors that could decrease DDR signals during iPS cell induction. We determined that Zscan4, in combination with the Yamanaka factors, not only remarkably reduced the DDR but also markedly promoted the efficiency of iPS cell generation. The inclusion of Zscan4 stabilized the genomic DNA, resulting in p53 downregulation. Furthermore, Zscan4 also enhanced telomere lengthening as early as 3 days post-infection through a telomere recombination-based mechanism. As a result, iPS cells generated with addition of Zscan4 exhibited longer telomeres than classical iPS cells. Strikingly, more than 50% of iPS cell lines (11/19) produced via this "Zscan4 protocol" gave rise to live-borne all-iPS cell mice as determined by TCA, compared to 1/12 for lines produced using the classical Yamanaka factors. Our findings provide the first demonstration that maintaining genomic stability during reprogramming promotes the generation of high quality iPS cells.

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“…Although it is essential to sequester the DNA end from nuclease and DNA repair activities for much of the cell cycle, during S phase the telomere must be made accessible to telomerase and the DNA replication machinery 1 .…”

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confidence: 99%

Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus

Anderson¹,

Kasher²,

Mayer³

et al. 2012

Nat Genet

242

237

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Coats plus is a highly pleiotropic disorder particularly affecting the eye, brain, bone and gastrointestinal tract. Here, we show that Coats plus results from mutations in CTC1, encoding conserved telomere maintenance component 1, a member of the mammalian homolog of the yeast heterotrimeric CST telomeric capping complex. Consistent with the observation of shortened telomeres in an Arabidopsis CTC1 mutant and the phenotypic overlap of Coats plus with the telomeric maintenance disorders comprising dyskeratosis congenita, we observed shortened telomeres in three individuals with Coats plus and an increase in spontaneous γH2AX-positive cells in cell lines derived from two affected individuals. CTC1 is also a subunit of the α-accessory factor (AAF) complex, stimulating the activity of DNA polymerase-α primase, the only enzyme known to initiate DNA replication in eukaryotic cells. Thus, CTC1 may have a function in DNA metabolism that is necessary for but not specific to telomeric integrity

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Telomeric Strategies: Means to an End

Cited by 185 publications

References 221 publications

A quantitative telomeric chromatin isolation protocol identifies different telomeric states

A quantitative telomeric chromatin isolation protocol identifies different telomeric states

Zscan4 promotes genomic stability during reprogramming and dramatically improves the quality of iPS cells as demonstrated by tetraploid complementation

Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus

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