Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Departments of Genomic Medicine and Neurosurgery, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Nucleic Acids Res. 2021 May 21;49(9):5084-5094. doi: 10.1093/nar/gkab276.
DNA cytosine methylation in mammals modulates gene expression and chromatin accessibility. It also impacts mutation rates, via spontaneous oxidative deamination of 5-methylcytosine (5mC) to thymine. In most cases the resulting T:G mismatches are repaired, following T excision by one of the thymine DNA glycosylases, TDG or MBD4. We found that C-to-T mutations are enriched in the binding sites of CCAAT/enhancer binding proteins (CEBP). Within a CEBP site, the presence of a T:G mismatch increased CEBPβ binding affinity by a factor of >60 relative to the normal C:G base pair. This enhanced binding to a mismatch inhibits its repair by both TDG and MBD4 in vitro. Furthermore, repair of the deamination product of unmethylated cytosine, which yields a U:G DNA mismatch that is normally repaired via uracil DNA glycosylase, is also inhibited by CEBPβ binding. Passage of a replication fork over either a T:G or U:G mismatch, before repair can occur, results in a C-to-T mutation in one of the daughter duplexes. Our study thus provides a plausible mechanism for accumulation of C-to-T human somatic mutations.
哺乳动物中的 DNA 胞嘧啶甲基化可调节基因表达和染色质可及性。它还通过 5-甲基胞嘧啶（5mC）自发氧化脱氨转化为胸腺嘧啶来影响突变率。在大多数情况下，所产生的 T:G 错配会被修复，方法是由胸腺嘧啶 DNA 糖基化酶 TDG 或 MBD4 切除 T。我们发现 C 到 T 的突变在 CCAAT/增强子结合蛋白（CEBP）的结合位点中富集。在一个 CEBP 位点中，与正常的 C:G 碱基对相比，T:G 错配使 CEBPβ 结合亲和力增加了 >60 倍。这种增强的错配结合抑制了 TDG 和 MBD4 在体外对其的修复。此外，CEBPβ 结合还抑制了对未甲基化胞嘧啶脱氨酶产物的修复，该产物会产生 U:G DNA 错配，通常通过尿嘧啶 DNA 糖基化酶修复。在修复发生之前，复制叉通过 T:G 或 U:G 错配通过，会导致一个子双链体中的 C 到 T 突变。因此，我们的研究为人类体细胞 C 到 T 突变的积累提供了一个合理的机制。
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