Immunology Program, Sloan Kettering Institute, New York, NY, 10065, USA.
Molecular Biology Program, Sloan-Kettering Institute, New York, NY, 10065, USA.
Nat Commun. 2022 Aug 2;13(1):4493. doi: 10.1038/s41467-022-32022-8.
Antibiotic resistance of Mycobacterium tuberculosis is exclusively a consequence of chromosomal mutations. Translesion synthesis (TLS) is a widely conserved mechanism of DNA damage tolerance and mutagenesis, executed by translesion polymerases such as DinBs. In mycobacteria, DnaE2 is the only known agent of TLS and the role of DinB polymerases is unknown. Here we demonstrate that, when overexpressed, DinB1 promotes missense mutations conferring resistance to rifampicin, with a mutational signature distinct from that of DnaE2, and abets insertion and deletion frameshift mutagenesis in homo-oligonucleotide runs. DinB1 is the primary mediator of spontaneous -1 frameshift mutations in homo-oligonucleotide runs whereas DnaE2 and DinBs are redundant in DNA damage-induced -1 frameshift mutagenesis. These results highlight DinB1 and DnaE2 as drivers of mycobacterial genome diversification with relevance to antimicrobial resistance and host adaptation.
结核分枝杆菌的抗生素耐药性完全是染色体突变的结果。跨损伤合成（TLS）是一种广泛保守的 DNA 损伤容忍和诱变机制，由跨损伤聚合酶如 DinB 执行。在分枝杆菌中，DnaE2 是唯一已知的 TLS 剂，而 DinB 聚合酶的作用尚不清楚。在这里，我们证明了当过度表达时，DinB1 会促进导致利福平耐药的错义突变，其突变特征与 DnaE2 不同，并促进同源寡核苷酸序列中的插入和缺失移码突变。DinB1 是同源寡核苷酸序列中自发 -1 移码突变的主要介导物，而 DnaE2 和 DinBs 在 DNA 损伤诱导的 -1 移码突变中是冗余的。这些结果突出了 DinB1 和 DnaE2 作为分枝杆菌基因组多样化的驱动因素，与抗微生物药物耐药性和宿主适应性有关。
