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Telomere dysfunction and mechanisms ...

Hackett, Jennifer Ann.

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Telomere dysfunction and mechanisms of genomic instability.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Telomere dysfunction and mechanisms of genomic instability./
作者:	Hackett, Jennifer Ann.
面頁冊數:	183 p.
附註:	Source: Dissertation Abstracts International, Volume: 64-02, Section: B, page: 0524.
Contained By:	Dissertation Abstracts International64-02B.
標題:	Biology, Genetics. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3080673

Telomere dysfunction and mechanisms of genomic instability.
Hackett, Jennifer Ann.

Telomere dysfunction and mechanisms of genomic instability. - 183 p.

Source: Dissertation Abstracts International, Volume: 64-02, Section: B, page: 0524.

Thesis (Ph.D.)--The Johns Hopkins University, 2003.

Chromosome rearrangements and region specific amplification and deletions occur frequently in cancer. This genomic instability begins early during tumorigenesis and the mechanisms underlying it are poorly understood. An increased tumor incidence in telomerase null mice suggests that telomere dysfunction induces genetic instability. To test this directly, we examined whether there was an increase in mutation rate in the absence of telomerase in S. cerevisiae . The mutation rate in the CAN1 gene increased 10--100 fold in est1Delta strains as telomeres became dysfunctional. This increased mutation rate resulted from an increased frequency of terminal deletions. These terminal deletions subsequently caused nonreciprocal translocations. At one locus, chromosomes with terminal deletions gained a new chromosome end through Rad52p-dependent, Rad51p-independent break induced replication. Interestingly, at a second locus, deletion of CAN1 was accompanied by more complicated rearrangements involving multiple chromosomes. These results established a role for telomere dysfunction in initiating genomic instability.Subjects--Topical Terms:

1017730
Biology, Genetics.

Telomere dysfunction and mechanisms of genomic instability.
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245 1 0 $a Telomere dysfunction and mechanisms of genomic instability.
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500 $a Source: Dissertation Abstracts International, Volume: 64-02, Section: B, page: 0524.
500 $a Sponsor: Carol Greider.
502 $a Thesis (Ph.D.)--The Johns Hopkins University, 2003.
520 $a Chromosome rearrangements and region specific amplification and deletions occur frequently in cancer. This genomic instability begins early during tumorigenesis and the mechanisms underlying it are poorly understood. An increased tumor incidence in telomerase null mice suggests that telomere dysfunction induces genetic instability. To test this directly, we examined whether there was an increase in mutation rate in the absence of telomerase in S. cerevisiae . The mutation rate in the CAN1 gene increased 10--100 fold in est1Delta strains as telomeres became dysfunctional. This increased mutation rate resulted from an increased frequency of terminal deletions. These terminal deletions subsequently caused nonreciprocal translocations. At one locus, chromosomes with terminal deletions gained a new chromosome end through Rad52p-dependent, Rad51p-independent break induced replication. Interestingly, at a second locus, deletion of CAN1 was accompanied by more complicated rearrangements involving multiple chromosomes. These results established a role for telomere dysfunction in initiating genomic instability.
520 $a We then set out to determine the mechanism by which dysfunctional telomeres cause genomic instability. One possible mechanism is end-to-end chromosome fusion and subsequent breakage of the dicentric chromosome. Another mechanism is exonucleolytic end resection of a chromosome beginning at a dysfunctional telomere. To distinguish between these mechanisms, we measured mutation rate and the extent of loss of heterozygosity in diploid yeast with telomere dysfunction. We hypothesized that chromosome fusions should cause terminal deletions throughout a chromosome arm, while end resection should cause terminal deletions at chromosome ends. To our surprise, the mutation rate was elevated predominantly near chromosome ends in est1Delta/est1Delta yeast, suggesting that end resection, rather than breakage of fused chromosomes, was the primary mechanism for the production of terminal deletions in cells with telomere dysfunction. In support of the hypothesis that end resection initiates genomic instability, deletion of the gene for the DNA damage-responsive exonuclease Exo1p reduced the mutation rate in yeast with dysfunctional telomeres. These results establish a molecular mechanism by which telomere dysfunction initiates chromosome rearrangements.
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