Journal article
The SMC5/6 complex prevents genotoxicity upon APOBEC3A-mediated replication stress
The EMBO journal, v 43(15), pp 3240-3255
01 Aug 2024
PMID: 38886582
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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.
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Details
- Title
- The SMC5/6 complex prevents genotoxicity upon APOBEC3A-mediated replication stress
- Creators
- Dylan F Fingerman - Washington University in St. LouisDavid R O'Leary - Center for Genome Integrity, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USAAva R Hansen - Washington University in St. LouisThi Tran - Washington University in St. LouisBrooke R Harris - Washington University in St. LouisRachel A DeWeerd - Washington University in St. LouisKatharina E Hayer - Children's Hospital of PhiladelphiaJiayi Fan - Memorial Sloan Kettering Cancer CenterEmily Chen - Memorial Sloan Kettering Cancer CenterMithila Tennakoon - Washington University in St. LouisAlice Meroni - Washington University in St. LouisJulia H Szeto - Children's Hospital of PhiladelphiaJessica Devenport - Washington University in St. LouisDanielle LaVigne - Washington University in St. LouisMatthew D Weitzman - Children's Hospital of PhiladelphiaOphir Shalem - University of PennsylvaniaJeffrey Bednarski - Washington University in St. LouisAlessandro Vindigni - Washington University in St. LouisXiaolan Zhao - Memorial Sloan Kettering Cancer CenterAbby M Green (Corresponding Author) - Washington University in St. Louis
- Publication Details
- The EMBO journal, v 43(15), pp 3240-3255
- Publisher
- Springer Nature
- Grant note
- R01CA248526 / HHS | National Institutes of Health (NIH) K08 CA212299 / NCI NIH HHS R01 CA248526 / NCI NIH HHS R01 CA200867 / NCI NIH HHS R03 NS111447 / NINDS NIH HHS R01CA237263 / HHS | National Institutes of Health (NIH) CA200867 / U.S. Department of Defense (DOD) P30 CA008748 / NCI NIH HHS R01 CA237263 / NCI NIH HHS T32 HL007088 / NHLBI NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- College of Medicine
- Web of Science ID
- WOS:001248612300003
- Scopus ID
- 2-s2.0-85196119964
- Other Identifier
- 991022202508204721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Cell Biology