Mammalian RAD52 Functions in Break-Induced Replication Repair of Collapsed DNA Replication Forks

• Published in: Molecular cell Vol. 64; no. 6; pp. 1127 - 1134
• Main Authors: Sotiriou, Sotirios K., Kamileri, Irene, Lugli, Natalia, Evangelou, Konstantinos, Da-Ré, Caterina, Huber, Florian, Padayachy, Laura, Tardy, Sebastien, Nicati, Noemie L., Barriot, Samia, Ochs, Fena, Lukas, Claudia, Lukas, Jiri, Gorgoulis, Vassilis G., Scapozza, Leonardo, Halazonetis, Thanos D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.12.2016; Cell Press
• Subjects: Adenomatous Polyposis Coli Protein - deficiency; Adenomatous Polyposis Coli Protein - genetics; Animals; break-induced replication; cancer; Cell Line, Tumor; Cell Proliferation - drug effects; CRISPR-Cas Systems; Cyclin E - genetics; Cyclin E - metabolism; DNA - genetics; DNA - metabolism; DNA Breaks, Double-Stranded; DNA recombination; DNA replication stress; G1 Phase; Gene Expression; Genomic Instability; Humans; Mice; Mice, Knockout; Nocodazole - pharmacology; Osteosarcoma - genetics; Osteosarcoma - metabolism; Osteosarcoma - mortality; Osteosarcoma - pathology; RAD52; Rad52 DNA Repair and Recombination Protein - antagonists & inhibitors; Rad52 DNA Repair and Recombination Protein - genetics; Rad52 DNA Repair and Recombination Protein - metabolism; Recombinational DNA Repair; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; S Phase; Short; Stress, Physiological; Survival Analysis; RAD52; cancer; DNA recombination; break-induced replication; DNA replication stress
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2016.10.038

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. [Display omitted] •Mammalian RAD52 is involved in the oncogene-induced DNA replication stress response•Mammalian RAD52 functions in the repair of collapsed DNA replication forks•Rad52 deficiency prolongs the lifespan of Apcmin/+ mice RAD52 is dispensable for life in mammals but is required for double-stranded break (DSB) repair in yeast. Sotiriou et al. now show that mammalian RAD52 plays an important role in response to DNA replication stress by mediating the repair of collapsed DNA replication forks.