Abstract:
:Telomeric regions of the genome are inherently difficult-to-replicate due to their propensity to generate DNA secondary structures and form nucleoprotein complexes that can impede DNA replication fork progression. Precisely how cells respond to DNA replication stalling within a telomere remains poorly characterized, largely due to the methodological difficulties in analysing defined stalling events in molecular detail. Here, we utilized a site-specific DNA replication barrier mediated by the 'Tus/Ter' system to define the consequences of DNA replication perturbation within a single telomeric locus. Through molecular genetic analysis of this defined fork-stalling event, coupled with the use of a genome-wide genetic screen, we identified an important role for the SUMO-like domain protein, Esc2, in limiting genome rearrangements at a telomere. Moreover, we showed that these rearrangements are driven by the combined action of the Mph1 helicase and the homologous recombination machinery. Our findings demonstrate that chromosomal context influences cellular responses to a stalled replication fork and reveal protective factors that are required at telomeric loci to limit DNA replication stress-induced chromosomal instability.
journal_name
Nucleic Acids Resjournal_title
Nucleic acids researchauthors
Jørgensen SW,Liberti SE,Larsen NB,Lisby M,Mankouri HW,Hickson IDdoi
10.1093/nar/gkz158subject
Has Abstractpub_date
2019-05-21 00:00:00pages
4597-4611issue
9eissn
0305-1048issn
1362-4962pii
5369941journal_volume
47pub_type
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