@article{Mertz01092023,
author = {Mertz, Tony M. and Rice-Reynolds, Elizabeth and Nguyen, Ly and Wood, Anna and Cordero, Cameron and Bray, Nicholas and Harcy, Victoria and Vyas, Rudri K. and Mitchell, Debra and Lobachev, Kirill and Roberts, Steven A.}, 
title = {Genetic inhibitors of APOBEC3B-induced mutagenesis},
volume = {33}, 
number = {9}, 
pages = {1568-1581}, 
year = {2023}, 
doi = {10.1101/gr.277430.122}, 
abstract ={The cytidine deaminases APOBEC3A (A3A) and APOBEC3B (A3B) are prominent mutators of human cancer genomes. However, tumor-specific genetic modulators of APOBEC-induced mutagenesis are poorly defined. Here, we used a screen to identify 61 gene deletions that increase A3B-induced mutations in yeast. We also determined whether each deletion was epistatic with Ung1 loss, which indicated whether the encoded factors participate in the homologous recombination (HR)–dependent bypass of A3B/Ung1-dependent abasic sites or suppress A3B-catalyzed deamination by protecting against aberrant formation of single-stranded DNA (ssDNA). We found that the mutation spectra of A3B-induced mutations revealed genotype-specific patterns of strand-specific ssDNA formation and nucleotide incorporation across APOBEC-induced lesions. Combining these three metrics, we were able to establish a multifactorial signature of APOBEC-induced mutations specific to (1) failure to remove H3K56 acetylation, (2) defective CTF18–RFC complex function, and (3) defective HR-mediated bypass of APOBEC-induced lesions. We extended these results by analyzing mutation data for human tumors and found BRCA1/2-deficient breast cancers display three- to fourfold more APOBEC-induced mutations. Mirroring our results in yeast, Rev1-mediated C-to-G substitutions are mainly responsible for increased APOBEC-signature mutations in BRCA1/2-deficient tumors, and these mutations associate with lagging strand synthesis during replication. These results identify important factors that influence DNA replication dynamics and likely the abundance of APOBEC-induced mutation during tumor progression. They also highlight a novel role for BRCA1/2 during HR-dependent lesion bypass of APOBEC-induced lesions during cancer cell replication.}, 
URL = {http://genome.cshlp.org/content/33/9/1568.abstract}, 
eprint = {http://genome.cshlp.org/content/33/9/1568.full.pdf+html}, 
journal = {Genome Research} 
}