Reactome: A Curated Pathway Database

Telomere maintenance (R-GGA-418124)

Species Gallus gallus

Summation

Chicken and human telomeres share many features including the sequence of telomeric repeats [(TTAGGG)n], the structure and function of telomerase and its components, differential telomerase activity profiles among cell types, age-related and division-dependent telomere shortening, the complement of binding proteins associated with the telomere and the role of telomerase in immortalization and cellular transformation.

Three to five percent of the chicken genome is telomeric DNA including both terminal and interstitial telomeric repeats, which is ten times that found in the human genome (Delany et al. 2000; Nanda et al. 2002; O'Hare and Delany 2009). The quantity of telomeric DNA is striking because the chicken genome is one-third the size of human (1.25 pg versus 3 pg per haploid genome) and the sequencing and assembly of the chicken genome indicate an overall reduction of repetitive DNA (International Chicken Genome Sequencing Consortium 2004). There are three classes of telomeric arrays in chicken: interstitial arrays of ~2 to 10 Kb, terminal arrays ranging from 10-40 Kb, and a second class of terminal arrays called mega-telomeres (also known as ultra-long) ranging from 50 Kb to several Mb (Delany et al. 2000). The mega-telomeres show evidence of a high meiotic recombination rate and genotype-specific variation (Delany et al. 2003; Rodrigue et al. 2005; O'Hare and Delany 2009). Despite these extremes in size and abundance, shown in the photomicrograph below, chicken telomeres closely resemble their human counterparts in sequence and organization (Nanda and Schmid 1994; Nikitina and Woodcock 2004).

Telomerase genes characterized in chicken include telomerase RNA (cTERC also known as cTR) and telomerase reverse transcriptase (cTERT) (Delany and Daniels 2003; Delany and Daniels 2004). Chicken TERC maps to GGA 9q and displays conservation of sequence, regulatory elements and synteny among viral, avian and mammalian genomes (Delany and Daniels 2003; Fragnet et al. 2003). The template (CR1) region of TERC is conserved between human and chicken (Chen et al. 2000). In addition to its role as the template for addition of telomeric sequence, TERC may be required for proliferation in DT40 cells as Faure et al. (2008) were unable to generate TERC-null DT40 cells by gene targeting. The chicken DT40 cell line was derived from an ALV transformed B cell lymphoma (Baba et al.1985) and possesses a high rate of homologous recombination. Therefore, it is widely used for transfection of genes or knockdown of expression to explore vertebrate gene function (Buerstedde et al. 1991; Winding and Berchtold 2001; Arakawa and Buerstedde 2006; Bachl et al. 2007).

The sequence and structure of the catalytic subunit cTERT, which maps to GGA 2q, is highly conserved with regions and motifs in common with human, Xenopus, mouse, rat and hamster TERTs (Delany and Daniels 2004). Chicken TERT (1346 amino acids) shares 45% amino acid identity with human TERT (1132 amino acids) (Delany and Daniels 2004). Interesting differences include a substantially larger region of the protein termed the flexible linker which is located near the N-terminus and includes 298 amino acids in chicken and only 155 in human. Comparisons between human and chicken 5' regulatory motifs are reviewed further in Delany and Daniels (2004). Both full length cTERT mRNA and numerous shorter mRNAs generated by alternative splicing have been described although the function of these splice variants remains to be clarified (Chang and Delany 2006; Hrdlickova et al. 2006).

In both chicken and human, telomerase activity in vivo is robust early in development, declines thereafter in most somatic tissues, yet remains active in renewable tissues (Taylor and Delany 2000). Telomerase activity is also present in most transformed cells examined thus far in both human and chicken (Newbold 2002; Swanberg and Delany 2003; Swanberg and Delany 2005). Telomerase component transcript analysis (gene expression) was examined and cTERC down-regulation correlates with absence of telomerase activity in telomerase negative cells, suggesting that cTERC may be the rate-limiting component in some cell types (O'Hare and Delany 2005; Swanberg and Delany 2005). Telomere shortening occurs in somatic tissues in vivo and correlates with age (Taylor and Delany 2000; Delany et al. 2003). Division-dependent telomere shortening is observed in non-immortalized, non-transformed chicken cells in vitro (Swanberg and Delany 2003).

In human, proteins involved in the protection of telomeres include the shelterin complex composed of TRF1, TRF2 and POT1 all of which recognize (TTAGGG)n sequence repeats and TIN2, TPP1 and RAP1 which are thought to interconnect with TRF1, TRF2 and POT1 (de Lange 2005; Palm and de Lange 2008). Known telomere-related proteins found in chicken include: TRF1 (Cooley et al. 2009), TRF2 (Konrad et al. 1999), POT1 (Wei and Price 2004), the chicken homolog of RAP1 (Tan and Price 2003) and tankyrases 1 and 2 (De Rycker et al. 2003).

The figure shows mitotic metaphase chromosomes from a UCD 001 (Red Jungle Fowl) female (2n=78, ZW) illustrating the chicken telomeric DNA profile. UCD 001 is the sequenced chicken genome (International Chicken Genome Sequencing Consortium 2004). (A) DAPI-stained mitotic metaphase chromosomes (blue) with autosomes 1-4, 9, and ZW sex chromosomes indicated. (B) The same metaphase displaying a FITC-labeled telomeric probe showing the telomeric DNA locations, including interstitial arrays (e.g., GGA 1 arrays located within chromosome arms and near the centromere), the typical terminal arrays, and mega-telomeres on GGA 9 and W.

Locations in the PathwayBrowser
Additional Information
Compartment nucleoplasm
GO Biological Process telomere maintenance (0000723)
Literature References
pubMedId Title Journal Year
17623896 Dt40 gene disruptions: a how-to for the design and the construction of targeting vectors Subcell Biochem 2006
2998040 Cell lines derived from avian lymphomas exhibit two distinct phenotypes Virology 1985
17675859 Biotechnology and the chicken B cell line DT40 Cytogenet Genome Res 2007
1913816 Increased ratio of targeted to random integration after transfection of chicken B cell lines Cell 1991
16806743 Complicated RNA splicing of chicken telomerase reverse transcriptase revealed by profiling cells both positive and negative for telomerase activity Gene 2006
10721988 Secondary structure of vertebrate telomerase RNA Cell 2000
19321665 Trf1 is not required for proliferation or functional telomere maintenance in chicken DT40 cells Mol Biol Cell 2009
16166375 Shelterin: the protein complex that shapes and safeguards human telomeres Genes Dev 2005
14970722 The chicken telomerase RNA gene: conservation of sequence, regulatory elements and synteny among viral, avian and mammalian genomes Cytogenet Genome Res 2003
15363846 The chicken telomerase reverse transcriptase (chTERT): molecular and cytogenetic characterization with a comparative analysis Gene 2004
12817446 Telomeres in the chicken: genome stability and chromosome ends Poult Sci 2003
11060464 Organization of telomere sequences in birds: evidence for arrays of extreme length and for in vivo shortening Cytogenet Cell Genet 2000
12589701 Vertebrate tankyrase domain structure and sterile alpha motif (SAM)-mediated multimerization Biochem J 2003
18308646 Ku70 prevents genome instability resulting from heterozygosity of the telomerase RNA component in a vertebrate tumour line DNA Repair (Amst) 2008
12719590 The RNA subunit of telomerase is encoded by Marek's disease virus J Virol 2003
16352553 Mechanism of telomerase activation by v-Rel and its contribution to transformation J Virol 2006
15592404 Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution Nature 2004
10571037 Cloning and characterisation of the chicken gene encoding the telomeric protein TRF2 Gene 1999
8222759 Localization of the telomeric (TTAGGG)n sequence in chicken (Gallus domesticus) chromosomes Cytogenet Cell Genet 1994
12424522 Distribution of telomeric (TTAGGG)(n) sequences in avian chromosomes Chromosoma 2002
12435851 The significance of telomerase activation and cellular immortalization in human cancer Mutagenesis 2002
15249582 Closed chromatin loops at the ends of chromosomes J Cell Biol 2004
23598659 Telomerase gene expression in the chicken: Telomerase RNA (TR) and reverse transcriptase (TERT) transcript profiles are tissue-specific and correlate with telomerase activity Age (Dordr) 2005
19890728 Genetic variation exists for telomeric array organization within and among the genomes of normal, immortalized, and transformed chicken systems Chromosome Res 2009
18680434 How shelterin protects mammalian telomeres Annu Rev Genet 2008
16170623 Meiotic instability of chicken ultra-long telomeres and mapping of a 2.8 megabase array to the W-sex chromosome Chromosome Res 2005
14970723 Dynamics of telomere erosion in transformed and non-transformed avian cells in vitro Cytogenet Genome Res 2003
15922407 Differential expression of genes associated with telomere length homeostasis and oncogenesis in an avian model Mech Ageing Dev 2005
14659874 The telomeric protein Rap1 is conserved in vertebrates and is expressed from a bidirectional promoter positioned between the Rap1 and KARS genes Gene 2003
11142683 Ontogeny of telomerase in chicken: impact of downregulation on pre- and postnatal telomere length in vivo Dev Growth Differ 2000
14966288 Cell cycle localization, dimerization, and binding domain architecture of the telomere protein cPot1 Mol Cell Biol 2004
11226459 The chicken B cell line DT40: a novel tool for gene disruption experiments J Immunol Methods 2001