APOBEC3A and APOBEC3B Preferentially Deaminate the Lagging Strand Template during DNA Replication.
APOBEC3A and APOBEC3B Preferentially Deaminate the Lagging Strand Template during DNA Replication.
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DOI：
10.1016/j.celrep.2016.01.021
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发表时间：
2016-02-16
期刊：
影响因子：
8.8
通讯作者：
Roberts SA
中科院分区：
文献类型：
--
作者：
Hoopes JI;Cortez LM;Mertz TM;Malc EP;Mieczkowski PA;Roberts SA
APOBEC家族胞苷脱氨酶最近被认为是癌症基因组的强大突变体。APOBECs是ssDNA特异性酶，如何进入染色体DNA尚不清楚。为了确定APOBECs的染色体ssDNA底物，我们在酵母模型系统中表达了APOBEC3A和APOBEC3B，这两种最可能介导癌症诱变的APOBECs。我们证明，使用突变报告和全基因组测序，APOBEC3A和APOBEC3B诱导的诱变主要是由于在DNA复制过程中的滞后链模板脱氨基。此外，我们的研究结果表明，复制叉稳定蛋白的遗传缺陷和复制应激的化学诱导大大增加了APOBEC3A和3B的诱变。总之，这些结果强烈表明，在DNA滞后链合成过程中形成的ssDNA是APOBEC的主要底物，并且可能是经历复制应激的人类癌症的主要底物。
APOBEC family cytidine deaminases have been recently implicated as powerful mutators of cancer genomes. How APOBECs, which are ssDNA specific enzymes, gain access to chromosomal DNA is unclear. To ascertain the chromosomal ssDNA substrates of the APOBECs, we expressed APOBEC3A and APOBEC3B, the two most probable APOBECs mediating cancer mutagenesis, in a yeast model system. We demonstrate, using mutation reporters and whole genome sequencing, that APOBEC3A- and APOBEC3B-induced mutagenesis primarily results from the deamination of the lagging strand template during DNA replication. Moreover, our results indicate that both genetic deficiencies in replication fork-stabilizing proteins and chemical induction of replication stress greatly augment the mutagenesis of APOBEC3A and 3B. Taken together, these results strongly indicate that ssDNA formed during DNA lagging strand synthesis is a major substrate for APOBECs and may be the principal substrate in human cancers experiencing replication stress.