Break-induced replication repair of damaged forks induces genomic duplications in human cells

Lorenzo Costantino, Sotirios K. Sotiriou, Juha K. Rantala, Simon Magin, Emil Mladenov, Thomas Helleday, James E. Haber, George Iliakis, Olli P. Kallioniemi, Thanos D. Halazonetis (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

201 Citations (Scopus)

Abstract

In budding yeast, one-ended DNA double-strand breaks (DSBs) and damaged replication forks are repaired by break-induced replication (BIR), a homologous recombination pathway that requires the Pol32 subunit of DNA polymerase delta. DNA replication stress is prevalent in cancer, but BIR has not been characterized in mammals. In a cyclin E overexpression model of DNA replication stress, POLD3, the human ortholog of POL32, was required for cell cycle progression and processive DNA synthesis. Segmental genomic duplications induced by cyclin E overexpression were also dependent on POLD3, as were BIR-mediated recombination events captured with a specialized DSB repair assay. We propose that BIR repairs damaged replication forks in mammals, accounting for the high frequency of genomic duplications in human cancers.
Original languageEnglish
Pages (from-to)88-91
JournalScience
Volume343
Issue number6166
DOIs
Publication statusPublished - 2013
MoE publication typeA1 Journal article-refereed

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Cyclin E
DNA Replication
Mammals
Genomic Segmental Duplications
DNA Polymerase III
Saccharomycetales
Double-Stranded DNA Breaks
Homologous Recombination
Genetic Recombination
Neoplasms
Cell Cycle
DNA

Cite this

Costantino, L., Sotiriou, S. K., Rantala, J. K., Magin, S., Mladenov, E., Helleday, T., ... Halazonetis, T. D. (2013). Break-induced replication repair of damaged forks induces genomic duplications in human cells. Science, 343(6166), 88-91. https://doi.org/10.1126/science.1243211
Costantino, Lorenzo ; Sotiriou, Sotirios K. ; Rantala, Juha K. ; Magin, Simon ; Mladenov, Emil ; Helleday, Thomas ; Haber, James E. ; Iliakis, George ; Kallioniemi, Olli P. ; Halazonetis, Thanos D. / Break-induced replication repair of damaged forks induces genomic duplications in human cells. In: Science. 2013 ; Vol. 343, No. 6166. pp. 88-91.
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title = "Break-induced replication repair of damaged forks induces genomic duplications in human cells",
abstract = "In budding yeast, one-ended DNA double-strand breaks (DSBs) and damaged replication forks are repaired by break-induced replication (BIR), a homologous recombination pathway that requires the Pol32 subunit of DNA polymerase delta. DNA replication stress is prevalent in cancer, but BIR has not been characterized in mammals. In a cyclin E overexpression model of DNA replication stress, POLD3, the human ortholog of POL32, was required for cell cycle progression and processive DNA synthesis. Segmental genomic duplications induced by cyclin E overexpression were also dependent on POLD3, as were BIR-mediated recombination events captured with a specialized DSB repair assay. We propose that BIR repairs damaged replication forks in mammals, accounting for the high frequency of genomic duplications in human cancers.",
author = "Lorenzo Costantino and Sotiriou, {Sotirios K.} and Rantala, {Juha K.} and Simon Magin and Emil Mladenov and Thomas Helleday and Haber, {James E.} and George Iliakis and Kallioniemi, {Olli P.} and Halazonetis, {Thanos D.}",
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Costantino, L, Sotiriou, SK, Rantala, JK, Magin, S, Mladenov, E, Helleday, T, Haber, JE, Iliakis, G, Kallioniemi, OP & Halazonetis, TD 2013, 'Break-induced replication repair of damaged forks induces genomic duplications in human cells', Science, vol. 343, no. 6166, pp. 88-91. https://doi.org/10.1126/science.1243211

Break-induced replication repair of damaged forks induces genomic duplications in human cells. / Costantino, Lorenzo; Sotiriou, Sotirios K.; Rantala, Juha K.; Magin, Simon; Mladenov, Emil; Helleday, Thomas; Haber, James E.; Iliakis, George; Kallioniemi, Olli P.; Halazonetis, Thanos D. (Corresponding Author).

In: Science, Vol. 343, No. 6166, 2013, p. 88-91.

Research output: Contribution to journalArticleScientificpeer-review

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AU - Costantino, Lorenzo

AU - Sotiriou, Sotirios K.

AU - Rantala, Juha K.

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AU - Mladenov, Emil

AU - Helleday, Thomas

AU - Haber, James E.

AU - Iliakis, George

AU - Kallioniemi, Olli P.

AU - Halazonetis, Thanos D.

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AB - In budding yeast, one-ended DNA double-strand breaks (DSBs) and damaged replication forks are repaired by break-induced replication (BIR), a homologous recombination pathway that requires the Pol32 subunit of DNA polymerase delta. DNA replication stress is prevalent in cancer, but BIR has not been characterized in mammals. In a cyclin E overexpression model of DNA replication stress, POLD3, the human ortholog of POL32, was required for cell cycle progression and processive DNA synthesis. Segmental genomic duplications induced by cyclin E overexpression were also dependent on POLD3, as were BIR-mediated recombination events captured with a specialized DSB repair assay. We propose that BIR repairs damaged replication forks in mammals, accounting for the high frequency of genomic duplications in human cancers.

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Costantino L, Sotiriou SK, Rantala JK, Magin S, Mladenov E, Helleday T et al. Break-induced replication repair of damaged forks induces genomic duplications in human cells. Science. 2013;343(6166):88-91. https://doi.org/10.1126/science.1243211