| Autor: |
Jordan Naumann, Prokopios Argyris, Michael Carpenter, Harshita Gupta, Yanjun Chen, Nuri Alpay Temiz, Yufan Zhou, Cameron Durfee, Joshua Proehl, Brenda Koniar, Silvestro Conticello, David Largaespada, William Brown, Hideki Aihara, Rachel Vogel, Reuben Harris |
| Rok vydání: |
2023 |
| Popis: |
Although the APOBEC3 family of single-stranded DNA cytosine deaminases are well-known as antiviral factors, these enzymes are rapidly gaining attention as prominent sources of mutation in cancer. APOBEC3 signature single base substitutions, C-to-T and C-to-G in TCA and TCT motifs, are evident in over 70% of human malignancies and dominate the mutational landscape of numerous individual tumors. Recent murine studies have established cause-and-effect relationships, with both human APOBEC3A and APOBEC3B proving capable of promoting tumor formation in vivo. Here, we investigate the molecular mechanism of APOBEC3A-driven tumor development using the murine Fah liver complementation and regeneration system. First, we show that APOBEC3A alone is capable of driving tumor development (without Tp53 knockdown as in prior studies). Second, we show that the catalytic glutamic acid residue of APOBEC3A (E72) is required for tumor formation. Third, we show that an APOBEC3A separation-of-function mutant with compromised DNA deamination activity and wildtype RNA editing activity is defective in promoting tumor formation. Collectively, these results indicate that APOBEC3A is a “master driver” that fuels tumor formation through a DNA deamination-dependent mechanism. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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