How telomerase and Dna2 govern the fate of chromosome ends in Saccharomyces cerevisiae.
View/ Open
Sukhareuski2020.pdf (6.569Mb)
Date
04/07/2020Item status
Restricted AccessEmbargo end date
04/07/2021Author
Sukhareuski, Andrei
Metadata
Abstract
Genome stability in eukaryotic cells relies heavily on their ability to differentiate
between telomeres - natural ends of linear chromosomes - and double strand
breaks (DSBs), pathological lesions which can occur throughout the stretch of
chromosomal DNA. The former are to be protected from fusions,
recombination and recognition by DNA damage response, whereas the latter
are to be detected by the checkpoint system and repaired by end joining or
homologous recombination. Due to the end replication problem, continually
dividing cells are confronted with an additional necessity to maintain stable
telomere length, which in most eukaryotes is fulfilled by telomerase.
Telomerase is downregulated in human somatic cells to limit their replicative
capacity and prevent malignization, forcing pre-malignant cells to seek ways
of re-establishing telomere length homeostasis. Most cancers perform it by
reactivating telomerase. Recently, Makovets group found a yeast model for
telomerase reactivation through aneuploidy in cells with temperature-induced
telomerase insufficiency. Given that aneuploidy is a common feature of
cancers, a deeper mechanistic understanding of aneuploidy-driven telomerase
reactivation in yeast may shed more light on cancer telomere biology.
In telomerase-negative cancers telomere attrition is counteracted by
alternative lengthening of telomeres (ALT). ALT is related to one of DSB repair
pathways - break-induced replication (BIR), which operates on single-ended
DSBs, such as those originating from broken replication forks. Phosphorylated
Pif1 helicase has been reported to be essential for BIR, but the molecular
mechanism of this requirement has not been ascertained. We found that the
need for phosphorylated Pif1 in BIR is alleviated in yeast expressing an Nterminally truncated Dna2 nuclease/helicase. In my work I aim to gain insights
into how yeast solve problems related to both natural chromosomal ends and
DSBs by investigating mechanisms underlying aneuploidy-dependent
telomerase reactivation in yeast cells with temperature-induced telomerase
insufficiency and by studying the genetic interaction between Dna2 and Pif1 in
BIR.