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Stabilization of Reversed Replication Forks by Telomerase Drives Telomere Catastrophe

Research output: Contribution to Journal/Magazine › Journal article › peer-review

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Stabilization of Reversed Replication Forks by Telomerase Drives Telomere Catastrophe. / Margalef, P.; Kotsantis, P.; Borel, V. et al.
In: Cell, Vol. 172, No. 3, 25.01.2018, p. 439-453.

Research output: Contribution to Journal/Magazine › Journal article › peer-review

Harvard

Margalef, P, Kotsantis, P, Borel, V, Bellelli, R, Panier, S & Boulton, SJ 2018, 'Stabilization of Reversed Replication Forks by Telomerase Drives Telomere Catastrophe', Cell, vol. 172, no. 3, pp. 439-453. https://doi.org/10.1016/j.cell.2017.11.047

APA

Margalef, P., Kotsantis, P., Borel, V., Bellelli, R., Panier, S., & Boulton, S. J. (2018). Stabilization of Reversed Replication Forks by Telomerase Drives Telomere Catastrophe. Cell, 172(3), 439-453. https://doi.org/10.1016/j.cell.2017.11.047

Vancouver

Margalef P, Kotsantis P, Borel V, Bellelli R, Panier S, Boulton SJ. Stabilization of Reversed Replication Forks by Telomerase Drives Telomere Catastrophe. Cell. 2018 Jan 25;172(3):439-453. doi: 10.1016/j.cell.2017.11.047

Author

Margalef, P. ; Kotsantis, P. ; Borel, V. et al. / Stabilization of Reversed Replication Forks by Telomerase Drives Telomere Catastrophe. In: Cell. 2018 ; Vol. 172, No. 3. pp. 439-453.

Bibtex

@article{77947ab3ef4c4db69979b217c8e93466,
title = "Stabilization of Reversed Replication Forks by Telomerase Drives Telomere Catastrophe",
abstract = "Telomere maintenance critically depends on the distinct activities of telomerase, which adds telomeric repeats to solve the end replication problem, and RTEL1, which dismantles DNA secondary structures at telomeres to facilitate replisome progression. Here, we establish that reversed replication forks are a pathological substrate for telomerase and the source of telomere catastrophe in Rtel1−/− cells. Inhibiting telomerase recruitment to telomeres, but not its activity, or blocking replication fork reversal through PARP1 inhibition or depleting UBC13 or ZRANB3 prevents the rapid accumulation of dysfunctional telomeres in RTEL1-deficient cells. In this context, we establish that telomerase binding to reversed replication forks inhibits telomere replication, which can be mimicked by preventing replication fork restart through depletion of RECQ1 or PARG. Our results lead us to propose that telomerase inappropriately binds to and inhibits restart of reversed replication forks within telomeres, which compromises replication and leads to critically short telomeres.",
keywords = "telomeres, telomerase, genome stability, Hoyeraal-Hreidarsson syndrome, replication fork reversal, RTEL1, PARP1, RECQ1, ZRANB3",
author = "P. Margalef and P. Kotsantis and V. Borel and R. Bellelli and S. Panier and S.J. Boulton",
year = "2018",
month = jan,
day = "25",
doi = "10.1016/j.cell.2017.11.047",
language = "English",
volume = "172",
pages = "439--453",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "3",

}

RIS

TY - JOUR

T1 - Stabilization of Reversed Replication Forks by Telomerase Drives Telomere Catastrophe

AU - Margalef, P.

AU - Kotsantis, P.

AU - Borel, V.

AU - Bellelli, R.

AU - Panier, S.

AU - Boulton, S.J.

PY - 2018/1/25

Y1 - 2018/1/25

N2 - Telomere maintenance critically depends on the distinct activities of telomerase, which adds telomeric repeats to solve the end replication problem, and RTEL1, which dismantles DNA secondary structures at telomeres to facilitate replisome progression. Here, we establish that reversed replication forks are a pathological substrate for telomerase and the source of telomere catastrophe in Rtel1−/− cells. Inhibiting telomerase recruitment to telomeres, but not its activity, or blocking replication fork reversal through PARP1 inhibition or depleting UBC13 or ZRANB3 prevents the rapid accumulation of dysfunctional telomeres in RTEL1-deficient cells. In this context, we establish that telomerase binding to reversed replication forks inhibits telomere replication, which can be mimicked by preventing replication fork restart through depletion of RECQ1 or PARG. Our results lead us to propose that telomerase inappropriately binds to and inhibits restart of reversed replication forks within telomeres, which compromises replication and leads to critically short telomeres.

AB - Telomere maintenance critically depends on the distinct activities of telomerase, which adds telomeric repeats to solve the end replication problem, and RTEL1, which dismantles DNA secondary structures at telomeres to facilitate replisome progression. Here, we establish that reversed replication forks are a pathological substrate for telomerase and the source of telomere catastrophe in Rtel1−/− cells. Inhibiting telomerase recruitment to telomeres, but not its activity, or blocking replication fork reversal through PARP1 inhibition or depleting UBC13 or ZRANB3 prevents the rapid accumulation of dysfunctional telomeres in RTEL1-deficient cells. In this context, we establish that telomerase binding to reversed replication forks inhibits telomere replication, which can be mimicked by preventing replication fork restart through depletion of RECQ1 or PARG. Our results lead us to propose that telomerase inappropriately binds to and inhibits restart of reversed replication forks within telomeres, which compromises replication and leads to critically short telomeres.

KW - telomeres

KW - telomerase

KW - genome stability

KW - Hoyeraal-Hreidarsson syndrome

KW - replication fork reversal

KW - RTEL1

KW - PARP1

KW - RECQ1

KW - ZRANB3

U2 - 10.1016/j.cell.2017.11.047

DO - 10.1016/j.cell.2017.11.047

M3 - Journal article

VL - 172

SP - 439

EP - 453

JO - Cell

JF - Cell

SN - 0092-8674

IS - 3

ER -