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Subcellular localization of the APOBEC3 proteins during mitosis and implications for genomic DNA deamination

机译：APOBEC3蛋白在有丝分裂过程中的亚细胞定位及其对基因组DNA脱氨的影响

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Humans have seven APO BEC3 DNA cytosine deaminases. The activity of these enzymes allows them to restrict a variety of retroviruses and retrotransposons, but may also cause pro-mutagenic genomic uracil lesions. During interphase the APO BEC3 proteins have different subcellular localizations: cell-wide, cytoplasmic or nuclear. This implies that only a subset of APO BEC3s have contact with nuclear DNA. However, during mitosis, the nuclear envelope breaks down and cytoplasmic proteins may enter what was formerly a privileged zone. To address the hypothesis that all APO BEC3 proteins have access to genomic DNA, we analyzed the localization of the APO BEC3 proteins during mitosis. We show that APO BEC3A, APO BEC3C and APO BEC3H are excluded from condensed chromosomes, but become cell-wide during telophase. However, APO BEC3B, APO BEC3D, APO BEC3F and APO BEC3G are excluded from chromatin throughout mitosis. After mitosis, APO BEC3B becomes nuclear, and APO BEC3D, APO BEC3F and APO BEC3G become cytoplasmic. Both structural motifs as well as size may be factors in regulating chromatin exclusion. Deaminase activity was not dependent on cell cycle phase. We also analyzed APO BEC3-induced cell cycle perturbations as a measure of each enzyme's capacity to inflict genomic DNA damage. AID, APO BEC3A and APO BEC3B altered the cell cycle profile, and, unexpectedly, APO BEC3D also caused changes. We conclude that several APO BEC3 family members have access to the nuclear compartment and can impede the cell cycle, most likely through DNA deamination and the ensuing DNA damage response. Such genomic damage may contribute to carcinogenesis, as demonstrated by AID in B cell cancers and, recently, APO BEC3B in breast cancers.
机译：人类有七个APO BEC3 DNA胞嘧啶脱氨酶。这些酶的活性使它们能够限制各种逆转录病毒和逆转座子，但也可能引起诱变的基因组尿嘧啶损伤。在相间期，APO BEC3蛋白具有不同的亚细胞定位：整个细胞，细胞质或细胞核。这意味着只有一部分APO BEC3与核DNA接触。但是，在有丝分裂过程中，核被膜破裂，细胞质蛋白可能进入原先的特权区域。为了解决所有APO BEC3蛋白都可访问基因组DNA的假设，我们分析了有丝分裂期间APO BEC3蛋白的定位。我们显示，APO BEC3A，APO BEC3C和APO BEC3H被从浓缩染色体中排除，但是在末期变成全细胞的。但是，整个有丝分裂期间，染色质均不包括APO BEC3B，APO BEC3D，APO BEC3F和APO BEC3G。有丝分裂后，APO BEC3B变成核，而APO BEC3D，APO BEC3F和APO BEC3G变成细胞质。结构基序和大小都可能是调节染色质排斥的因素。脱氨酶活性不依赖于细胞周期阶段。我们还分析了APO BEC3诱导的细胞周期扰动，以衡量每种酶对基因组DNA造成破坏的能力。 AID，APO BEC3A和APO BEC3B改变了细胞周期谱，出乎意料的是，APO BEC3D也引起了变化。我们得出的结论是，一些APO BEC3家族成员可以进入核区室，并可能通过DNA脱氨和随后的DNA损伤反应来阻碍细胞周期。如B细胞癌中的AID以及最近在乳腺癌中的APO BEC3B所表明的，这种基因组损伤可能会导致癌变。

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