Defective DNA polymerase beta invoke a cytosolic DNA mediated inflammatory response.
Defective DNA polymerase beta invoke a cytosolic DNA mediated inflammatory response.
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DOI：
10.3389/fimmu.2022.1039009
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
碱基切除修复(BER)是为了在内源性和外源性因素引起DNA碱基损伤后维持DNA基因组的完整性而发展起来的。相反，异常的BER会导致基因组不稳定，促进恶性转化，甚至会引发癌症的发展。以前，我们已经证明脱氧核糖核酸5‘-磷酸裂解酶(DRP)裂解酶缺陷的DNA聚合酶β(POLB)会导致复制相关的基因组不稳定性和对内源和外源DNA损伤剂的敏感性。具体地说，已经证实这种DRP裂解酶功能的丧失促进了炎症相关性胃癌的发生。然而，POLB异常对免疫信号和炎症反应的影响机制尚不清楚。在这里，我们发现POLB的DRP裂解酶缺陷变体(Leu22Pro，或L22P)增加了与有丝分裂功能障碍相关的基因组不稳定性，最终导致胞浆DNA介导的炎症反应。此外，多聚ADP-核糖聚合酶1的抑制加剧了染色体的不稳定性，并增强了胞质DNA介导的炎症反应。我们的结果表明POLB在调节炎症信号方面发挥了重要作用，并为未来潜在的癌症免疫治疗提供了机制基础。
Base excision repair (BER) has evolved to maintain the genomic integrity of DNA following endogenous and exogenous agent induced DNA base damage. In contrast, aberrant BER induces genomic instability, promotes malignant transformation and can even trigger cancer development. Previously, we have shown that deoxyribo-5′-phosphate (dRP) lyase deficient DNA polymerase beta (POLB) causes replication associated genomic instability and sensitivity to both endogenous and exogenous DNA damaging agents. Specifically, it has been established that this loss of dRP lyase function promotes inflammation associated gastric cancer. However, the way that aberrant POLB impacts the immune signaling and inflammatory responses is still unknown. Here we show that a dRP lyase deficient variant of POLB (Leu22Pro, or L22P) increases mitotic dysfunction associated genomic instability, which eventually leads to a cytosolic DNA mediated inflammatory response. Furthermore, poly(ADP-ribose) polymerase 1 inhibition exacerbates chromosomal instability and enhances the cytosolic DNA mediated inflammatory response. Our results suggest that POLB plays a significant role in modulating inflammatory signaling, and they provide a mechanistic basis for future potential cancer immunotherapies.
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影响因子：
9
作者：
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影响因子：
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通讯作者：
Vindigni, Alessandro
影响因子：
56.9
作者：
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通讯作者：
AMES, BN
DOI：
10.1038/nrm.2017.53
发表时间：
2017-10
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Ray Chaudhuri A;Nussenzweig A
通讯作者：
Nussenzweig A
DOI：
10.1083/jcb.201708069
发表时间：
2017-10-02
期刊：
The Journal of cell biology
影响因子：
--
作者：
Gekara NO
通讯作者：
Gekara NO