TY - JOUR
T1 - Mammalian RAD52 Functions in Break-Induced Replication Repair of Collapsed DNA Replication Forks
AU - Sotiriou, Sotirios K.
AU - Kamileri, Irene
AU - Lugli, Natalia
AU - Evangelou, Konstantinos
AU - Da-Ré, Caterina
AU - Huber, Florian
AU - Padayachy, Laura
AU - Tardy, Sebastien
AU - Nicati, Noemie L.
AU - Barriot, Samia
AU - Ochs, Fena
AU - Lukas, Claudia
AU - Lukas, Jiri
AU - Gorgoulis, Vasileios
AU - Scapozza, Leonardo
AU - Halazonetis, Thanos D.
PY - 2016/12/15
Y1 - 2016/12/15
N2 - Human cancers are characterized by the presence of oncogene-induced DNA replication stress (DRS), making them dependent on repair pathways such as break-induced replication (BIR) for damaged DNA replication forks. To better understand BIR, we performed a targeted siRNA screen for genes whose depletion inhibited G1 to S phase progression when oncogenic cyclin E was overexpressed. RAD52, a gene dispensable for normal development in mice, was among the top hits. In cells in which fork collapse was induced by oncogenes or chemicals, the Rad52 protein localized to DRS foci. Depletion of Rad52 by siRNA or knockout of the gene by CRISPR/Cas9 compromised restart of collapsed forks and led to DNA damage in cells experiencing DRS. Furthermore, in cancer-prone, heterozygous APC mutant mice, homozygous deletion of the Rad52 gene suppressed tumor growth and prolonged lifespan. We therefore propose that mammalian RAD52 facilitates repair of collapsed DNA replication forks in cancer cells.
AB - Human cancers are characterized by the presence of oncogene-induced DNA replication stress (DRS), making them dependent on repair pathways such as break-induced replication (BIR) for damaged DNA replication forks. To better understand BIR, we performed a targeted siRNA screen for genes whose depletion inhibited G1 to S phase progression when oncogenic cyclin E was overexpressed. RAD52, a gene dispensable for normal development in mice, was among the top hits. In cells in which fork collapse was induced by oncogenes or chemicals, the Rad52 protein localized to DRS foci. Depletion of Rad52 by siRNA or knockout of the gene by CRISPR/Cas9 compromised restart of collapsed forks and led to DNA damage in cells experiencing DRS. Furthermore, in cancer-prone, heterozygous APC mutant mice, homozygous deletion of the Rad52 gene suppressed tumor growth and prolonged lifespan. We therefore propose that mammalian RAD52 facilitates repair of collapsed DNA replication forks in cancer cells.
KW - break-induced replication
KW - cancer
KW - DNA recombination
KW - DNA replication stress
KW - RAD52
UR - http://www.scopus.com/inward/record.url?scp=85008222788&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2016.10.038
DO - 10.1016/j.molcel.2016.10.038
M3 - Article
AN - SCOPUS:85008222788
SN - 1097-2765
VL - 64
SP - 1127
EP - 1134
JO - Molecular Cell
JF - Molecular Cell
IS - 6
ER -
