Esc2 promotes telomere stability in response to DNA replication stress
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Esc2 promotes telomere stability in response to DNA replication stress. / Jørgensen, Signe W.; Liberti, Sascha E.; Larsen, Nicolai B.; Lisby, Michael; Mankouri, Hocine W.; Hickson, Ian D.
In: Nucleic Acids Research, Vol. 47, No. 9, 2019, p. 4597-4611.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Esc2 promotes telomere stability in response to DNA replication stress
AU - Jørgensen, Signe W.
AU - Liberti, Sascha E.
AU - Larsen, Nicolai B.
AU - Lisby, Michael
AU - Mankouri, Hocine W.
AU - Hickson, Ian D.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
U2 - 10.1093/nar/gkz158
DO - 10.1093/nar/gkz158
M3 - Journal article
C2 - 30838410
AN - SCOPUS:85066028497
VL - 47
SP - 4597
EP - 4611
JO - Nucleic Acids Research
JF - Nucleic Acids Research
SN - 0305-1048
IS - 9
ER -
ID: 226793374