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Break-Induced Replication Repair of Damaged Forks Induces Genomic Duplications in Human Cells

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

in animal ovaries / Biotechnology / breasts / Cell Cycle / Cell growth / Cell lines / Cyclin E - biosynthesis / Cyclin E - genetics / Cyclins / Deoxyribonucleic acid / DNA / DNA Breaks, Double-Stranded / DNA damage / DNA Polymerase III - genetics / DNA Polymerase III - physiology / DNA repair / DNA Repair - genetics / DNA replication / DNA Replication - genetics / DNA-directed DNA polymerase / Epithelial cells / Gene Duplication / Genomics / Humans / Mammals / neoplasm cells / Neoplasms - genetics / oncogenes / ovarian neoplasms / plant ovary / Small interfering RNA / Studies / Yeasts

2014

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Break-Induced Replication Repair of Damaged Forks Induces Genomic Duplications in Human Cells

2014

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Break-Induced Replication Repair of Damaged Forks Induces Genomic Duplications in Human Cells

2014

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Journal Article

Break-Induced Replication Repair of Damaged Forks Induces Genomic Duplications in Human Cells

Kallioniemi, Olli P.,

Costantino, Lorenzo,

Rantala, Juha K.,

Sotiriou, Sotirios K.,

Haber, James E.,

Iliakis, George,

Halazonetis, Thanos D.,

Helleday, Thomas,

Magin, Simon,

Mladenov, Emil

2014

Overview

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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Publisher

American Association for the Advancement of Science,The American Association for the Advancement of Science

Subject

/ breasts

/ Cyclin E - biosynthesis