Replication catastrophe induced by cyclic hypoxia leads to increased APOBEC3B activity.
Replication catastrophe induced by cyclic hypoxia leads to increased APOBEC3B activity.
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DOI：
10.1093/nar/gkab551
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发表时间：
2021-07-21
影响因子：
14.9
通讯作者：
Hammond EM
中科院分区：
文献类型：
--
作者：
Bader SB;Ma TS;Simpson CJ;Liang J;Maezono SEB;Olcina MM;Buffa FM;Hammond EM
肿瘤的异质性包括可变和波动的氧浓度，这导致在大多数实体肿瘤中积累缺氧区。肿瘤缺氧导致治疗耐药性增加，并与基因组不稳定有关。在这里，我们测试了一种假设，即暴露在导致复制应激的低氧水平可以增加APOBEC的活性和APOBEC介导的突变的积累。APOBEC依赖的突变特征已经被很好地描述，尽管支撑它们的生理条件还没有被描述。我们证明了导致复制灾难的波动/循环低氧条件诱导了APOBEC3B的表达和活性。相反，在没有DNA损伤的情况下诱导复制应激的稳定/慢性低氧条件不足以诱导APOBEC3B。最重要的是，患者肿瘤中APOBEC介导的突变的数量与缺氧特征相关。总之，我们的数据支持这一结论，即低氧诱导的复制灾难导致肿瘤基因组不稳定，特别是通过增加APOBEC3B的活性。
Tumor heterogeneity includes variable and fluctuating oxygen concentrations, which result in the accumulation of hypoxic regions in most solid tumors. Tumor hypoxia leads to increased therapy resistance and has been linked to genomic instability. Here, we tested the hypothesis that exposure to levels of hypoxia that cause replication stress could increase APOBEC activity and the accumulation of APOBEC-mediated mutations. APOBEC-dependent mutational signatures have been well-characterized, although the physiological conditions which underpin them have not been described. We demonstrate that fluctuating/cyclic hypoxic conditions which lead to replication catastrophe induce the expression and activity of APOBEC3B. In contrast, stable/chronic hypoxic conditions which induce replication stress in the absence of DNA damage are not sufficient to induce APOBEC3B. Most importantly, the number of APOBEC-mediated mutations in patient tumors correlated with a hypoxia signature. Together, our data support the conclusion that hypoxia-induced replication catastrophe drives genomic instability in tumors, specifically through increasing the activity of APOBEC3B.
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影响因子：
30.8
作者：
Burns, Michael B.;Temiz, Nuri A.;Harris, Reuben S.
通讯作者：
Harris, Reuben S.
染色体不稳定性通过胞质DNA反应驱动转移。
影响因子：
64.8
作者：
Bakhoum SF;Ngo B;Laughney AM;Cavallo JA;Murphy CJ;Ly P;Shah P;Sriram RK;Watkins TBK;Taunk NK;Duran M;Pauli C;Shaw C;Chadalavada K;Rajasekhar VK;Genovese G;Venkatesan S;Birkbak NJ;McGranahan N;Lundquist M;LaPlant Q;Healey JH;Elemento O;Chung CH;Lee NY;Imielenski M;Nanjangud G;Pe'er D;Cleveland DW;Powell SN;Lammerding J;Swanton C;Cantley LC
通讯作者：
Cantley LC
DOI：
10.1186/s13058-014-0498-3
发表时间：
2015-01-21
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Harris RS
通讯作者：
Harris RS
影响因子：
64.5
作者：
Haradhvala NJ;Polak P;Stojanov P;Covington KR;Shinbrot E;Hess JM;Rheinbay E;Kim J;Maruvka YE;Braunstein LZ;Kamburov A;Hanawalt PC;Wheeler DA;Koren A;Lawrence MS;Getz G
通讯作者：
Getz G
影响因子：
13.6
作者：
Law EK;Sieuwerts AM;LaPara K;Leonard B;Starrett GJ;Molan AM;Temiz NA;Vogel RI;Meijer-van Gelder ME;Sweep FC;Span PN;Foekens JA;Martens JW;Yee D;Harris RS
通讯作者：
Harris RS