Onset of deaminase APOBEC3B induction in response to DNA double-strand breaks.
Onset of deaminase APOBEC3B induction in response to DNA double-strand breaks.
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DOI：
10.1016/j.bbrep.2018.10.010
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发表时间：
2018-12
影响因子：
2.7
通讯作者：
Yoshioka KI
中科院分区：
文献类型：
--
作者：
Shimizu A;Fujimori H;Minakawa Y;Matsuno Y;Hyodo M;Murakami Y;Yoshioka KI
5-甲基胞嘧啶的脱氨基是炎症相关癌症致癌突变的主要原因。脱氨酶APOBEC3B在这些癌症中表达，并在复制应激下引起突变；然而，APOBEC3B介导脱氨的机制及其与基因组疾病的关系仍不清楚。在这里，我们证明了APOBEC3B是稳定的，以诱导脱胺反应，以响应DNA双链断裂(DSB)，导致形成长期的DSB。尿嘧啶是主要的脱氨产物，随后通过尿嘧啶-DNA糖基酶2(UNG2)被碱基切除修复(BER)靶向；因此，迟发性DSB作为BER的副产物出现。用PARP抑制剂处理细胞后，这些延迟DSB的频率增加，而在UNG2被敲除后，延迟DSB的频率被抑制。迟发性DSB以ATR依赖的方式诱发。与γ射线照射直接引起的DSB不同，这些继发性DSB是持续性的。总体而言，这些结果表明，脱氨酶APOBEC3B是对DSB的响应诱导的，除了诱变的5ME-C>；T转换诱导外，还导致长时间DSB的形成。APOBEC3B是稳定的，以诱导脱氨反应响应DSB。去氨基作用通过UNG2介导的BER导致迟发性DSB的形成。以ATR依赖的方式诱导的迟发性DSB是持久的。
Deamination of 5-methyl cytosine is a major cause of cancer-driver mutations in inflammation-associated cancers. The deaminase APOBEC3B is expressed in these cancers and causes mutations under replication stress; however, the mechanisms by which APOBEC3B mediates deamination and its association with genomic disorders are still unclear. Here, we show that APOBEC3B is stabilized to induce deamination reaction in response to DNA double-strand breaks (DSBs), resulting in the formation of long-lasting DSBs. Uracil, the major deamination product, is subsequently targeted by base excision repair (BER) through uracil-DNA glycosylase 2 (UNG2); hence late-onset DSBs arise as by-products of BER. The frequency of these delayed DSBs was increased by treatment of cells with a PARP inhibitor, and was suppressed following knock-down of UNG2. The late-onset DSBs were induced in an ATR-dependent manner. Those secondary DSBs were persistent, unlike DSBs directly caused by γ-ray irradiation. Overall, these results suggest that the deaminase APOBEC3B is induced in response to DSBs, leading to long-lasting DSB formation in addition to mutagenic 5me-C>T transition induction. APOBEC3B is stabilized to induce deamination reaction in response to DSBs. Deamination leads to formation of late-onset DSBs through UNG2-mediated BER. Late-onset DSBs induced in an ATR-dependent manner are persistent.
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