TY - JOUR
T1 - Break-induced replication repair of damaged forks induces genomic duplications in human cells
AU - Costantino, Lorenzo
AU - Sotiriou, Sotirios K.
AU - Rantala, Juha K.
AU - Magin, Simon
AU - Mladenov, Emil
AU - Helleday, Thomas
AU - Haber, James E.
AU - Iliakis, George
AU - Kallioniemi, Olli P.
AU - Halazonetis, Thanos D.
PY - 2013
Y1 - 2013
N2 - 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.
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.
U2 - 10.1126/science.1243211
DO - 10.1126/science.1243211
M3 - Article
SN - 0036-8075
VL - 343
SP - 88
EP - 91
JO - Science
JF - Science
IS - 6166
ER -