Consider what you have learned about the telomeres found at the ends of eukaryot
ID: 23662 • Letter: C
Question
Consider what you have learned about the telomeres found at the ends of eukaryotic chromosomes and answer the following questions.a. Describe briefly the sequence composition of telomeric DNA sequences.
b. what functional role is servedby telomeres
c.Explain how telomerase replicates eukaryotic telomores.
d.Why is telomerase typically active in germ cells but not active in somatic cells
Explanation / Answer
The loss of telomere function can result in telomeric fusion events that lead to the types of genomic rearrangements, such as nonreciprocal translocations, that typify early-stage carcinogenesis. By using single-molecule approaches to characterize fusion events, we provide a functional definition of fusogenic telomeres in human cells. We show that approximately half of the fusion events contained no canonical telomere repeats at the fusion point; of those that did, the longest was 12.8 repeats. Furthermore, in addition to end-replication losses, human telomeres are subjected to large-scale deletion events that occur in the presence or absence of telomerase. Here we show that these telomeres are fusogenic, and thus despite the majority of telomeres being maintained at a stable length in normal human cells, a subset of stochastically shortened telomeres can potentially cause chromosomal instability. Telomere fusion was accompanied by the deletion of one or both telomeres extending several kilobases into the telomere-adjacent DNA, and microhomology was observed at the fusion points. This contrasted with telomere fusion that was observed following the experimental disruption of TRF2. The distinct error-prone mutational profile of fusion between critically shortened telomeres in human cells was reminiscent of Ku-independent microhomology-mediated end-joining. B Telomeres are the structures that cap the ends of linear chromosomes. In humans, they are composed of the hexameric DNA sequence TTAGGG tandemly repeated into arrays of up to 25 kb. In human cells, telomeric function is conferred by a complex of proteins that associate with telomeres via interactions with the key TTAGGG repeat-binding proteins TRF1, TRF2, and Pot1 (Chong et al. 1995; Broccoli et al. 1997; Baumann and Cech 2001). Telomeres prevent the natural end of the chromosome from being recognized as a double-stranded DNA break (d’Adda di Fagagna et al. 2003) and counteract the end-replication losses that occur as a consequence of semiconservative replication of linear DNA molecules (Olovnikov 1971; Harley et al. 1990). This function is mediated by the reverse transcriptase telomerase, which catalyzes the RNA-templated addition of telomere repeats de novo at the chromosomal terminus (Greider and Blackburn 1985). The majority of human somatic cells do not express sufficient levels of telomerase to counteract end-replication losses, and thus telomeric sequences erode at a rate of ~60–120 base pairs (bp) per cell division (Harley et al. 1990; Baird et al. 2003). Telomerase is expressed at high levels in immortal cell lines, the stem cell compartments of actively proliferating tissues, and >90% of human malignancies (Kim et al. 1994; Kolquist et al. 1998). C Gross chromosomal rearrangements are common during epithelial carcinogenesis (Mitelman et al. 1997; Shih et al. 2001). They occur early in tumor development, after which the genome appears to stabilize with advancing malignancy, roughly coincident with the activation of telomerase (Kim et al. 1994; Chadeneau et al. 1995; Meyerson et al. 1997). Late-generation telomerase knockout mice (terc-/-) show telomere loss, genomic instability, a higher rate of tumor formation, and a lower age of onset (Rudolph et al. 1999; O’Hagan et al. 2002). Crossing telomerase knockout mice with long telomeres with those with short telomeres revealed that fusion occurred preferentially between chromosomes containing the short telomeres (Hemann et al. 2001). Tumors derived from terc-/- p53+/- mice contain high frequencies of chromosomes lacking telomeric signals, anaphase bridges, nonreciprocal translocations, and end-to-end fusions (Artandi et al. 2000). Thus, short dysfunctional telomeres can drive the earliest stages of cancer; indeed, telomere dysfunction has been proposed to contribute to the nonreciprocal translocations that are common in adult carcinomas (Atkin 1986; Gisselsson et al. 2001, 2004; Rudolph et al. 2001). D he end-capping function of human telomeres is mediated by TRF2 and associated proteins (van Steensel et al. 1998). Inhibition of TRF2 function results in telomere fusion events that are dependent on factors involved in nonhomologous end-joining (NHEJ) (Smogorzewska et al. 2002; Celli and de Lange 2005). These types of fusion usually contain many kilobases of telomeric repeat DNA (van Steensel et al. 1998) and result from the covalent linkage of the G-strand of one chromosome end to the C-strand of the other (Smogorzewska et al. 2002). These data are consistent with a role of TRF2 in preventing aberrant fusion of functional telomeres by NHEJ. However, in contrast to TRF2-deficient cells, telomere fusion has been observed between short telomeres in the absence of NHEJ components (Baumann and Cech 2000; Heacock et al. 2004; Maser et al. 2007). Thus, the mechanistic basis of fusion between critically shortened telomeres in human cells is still unclear.
Related Questions
drjack9650@gmail.com
Navigate
Integrity-first tutoring: explanations and feedback only — we do not complete graded work. Learn more.