The SMC5/6 complex prevents genotoxicity upon APOBEC3A-mediated replication stress.

Autor:	Fingerman DF; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.; Center for Genome Integrity, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA., O'Leary DR; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.; Center for Genome Integrity, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA., Hansen AR; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.; Center for Genome Integrity, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.; Drexel University College of Medicine, Philadelphia, PA, USA., Tran T; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.; Center for Genome Integrity, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA., Harris BR; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.; Center for Genome Integrity, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA., DeWeerd RA; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.; Center for Genome Integrity, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA., Hayer KE; Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA, USA., Fan J; Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA., Chen E; Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.; School of Agriculture and Life Sciences, Cornell University, Ithaca, NY, USA., Tennakoon M; Center for Genome Integrity, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.; Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA., Meroni A; Center for Genome Integrity, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.; Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA., Szeto JH; Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, PA, USA., Devenport J; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.; Center for Genome Integrity, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA., LaVigne D; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.; Center for Genome Integrity, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA., Weitzman MD; Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA., Shalem O; Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA., Bednarski J; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.; Center for Genome Integrity, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA., Vindigni A; Center for Genome Integrity, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.; Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA., Zhao X; Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA., Green AM; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA. abby.green@wustl.edu.; Center for Genome Integrity, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA. abby.green@wustl.edu.
Jazyk:	angličtina
Zdroj:	The EMBO journal [EMBO J] 2024 Aug; Vol. 43 (15), pp. 3240-3255. Date of Electronic Publication: 2024 Jun 17.
DOI:	10.1038/s44318-024-00137-x
Abstrakt:	Mutational patterns caused by APOBEC3 cytidine deaminase activity are evident throughout human cancer genomes. In particular, the APOBEC3A family member is a potent genotoxin that causes substantial DNA damage in experimental systems and human tumors. However, the mechanisms that ensure genome stability in cells with active APOBEC3A are unknown. Through an unbiased genome-wide screen, we define the Structural Maintenance of Chromosomes 5/6 (SMC5/6) complex as essential for cell viability when APOBEC3A is active. We observe an absence of APOBEC3A mutagenesis in human tumors with SMC5/6 dysfunction, consistent with synthetic lethality. Cancer cells depleted of SMC5/6 incur substantial genome damage from APOBEC3A activity during DNA replication. Further, APOBEC3A activity results in replication tract lengthening which is dependent on PrimPol, consistent with re-initiation of DNA synthesis downstream of APOBEC3A-induced lesions. Loss of SMC5/6 abrogates elongated replication tracts and increases DNA breaks upon APOBEC3A activity. Our findings indicate that replication fork lengthening reflects a DNA damage response to APOBEC3A activity that promotes genome stability in an SMC5/6-dependent manner. Therefore, SMC5/6 presents a potential therapeutic vulnerability in tumors with active APOBEC3A. (© 2024. The Author(s).)
Databáze:	MEDLINE
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