The SMC5/6 complex prevents genotoxicity upon APOBEC3A-mediated replication stress Journal Article
| Authors: | Fingerman, D. F.; O’Leary, D. R.; Hansen, A. R.; Tran, T.; Harris, B. R.; DeWeerd, R. A.; Hayer, K. E.; Fan, J.; Chen, E.; Tennakoon, M.; Meroni, A.; Szeto, J. H.; Devenport, J.; LaVigne, D.; Weitzman, M. D.; Shalem, O.; Bednarski, J.; Vindigni, A.; Zhao, X.; Green, A. M. |
| Article Title: | The SMC5/6 complex prevents genotoxicity upon APOBEC3A-mediated replication stress |
| 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. © The Author(s) 2024. |
| Keywords: | controlled study; unclassified drug; human cell; genetics; dna replication; dna synthesis; polymerase chain reaction; proteins; cell cycle protein; nonhistone protein; metabolism; cell cycle proteins; chromosomal proteins, non-histone; dna damage; diagnostic procedure; protein; small interfering rna; genome-wide association study; cancer cell culture; immunofluorescence; cell line, tumor; cytidine deaminase; genomic instability; tumor cell line; lentivirus vector; immunoblotting; dna extraction; short hairpin rna; mutagenesis; genomic dna; genotoxicity; dna damage checkpoint; cell synchronization; comet assay; genome integrity; replication stress; humans; human; article; rna sequencing; cell viability assay; cell cycle assay; mutational signatures; hct 116 cell line; cell proliferation assay; jurkat cell line; u2os cell line; k-562 cell line; cancer mutagenesis; apobec3a protein, human; crispr associated endonuclease cas9; immunosignature; apolipoprotein b mrna editing enzyme catalytic polypeptide like 3a; structural maintenance of chromosomes 5; structural maintenance of chromosomes 6; smc5 protein, human; smc6 protein, human; dna fiber assay; mutational signature analysis |
| Journal Title: | EMBO Journal |
| Volume: | 43 |
| Issue: | 15 |
| ISSN: | 0261-4189 |
| Publisher: | Wiley Blackwell |
| Date Published: | 2024-08-01 |
| Start Page: | 3240 |
| End Page: | 3255 |
| Language: | English |
| DOI: | 10.1038/s44318-024-00137-x |
| PUBMED: | 38886582 |
| PROVIDER: | scopus |
| PMCID: | PMC11294446 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed -- Source: Scopus |
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