Atypical genotoxicity of carcinogenic nickel(II): Linkage to dNTP biosynthesis, DNA-incorporated rNMPs, and impaired repair of TOP1-DNA crosslinks.
Atypical genotoxicity of carcinogenic nickel(II): Linkage to dNTP biosynthesis, DNA-incorporated rNMPs, and impaired repair of TOP1-DNA crosslinks.
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DOI：
10.1016/j.jbc.2023.105385
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发表时间：
2023-12
影响因子：
4.8
通讯作者：
Zhitkovich, Anatoly
中科院分区：
文献类型：
--
作者：
Krawic, Casey;Luczak, Michal W.;Valiente, Sophia;Zhitkovich, Anatoly
癌症是一种遗传性疾病，其发展需要多种突变。然而，许多致癌物是DNA非反应性和非致突变性的，因此被描述为非遗传毒性。其中一种致癌物质是镍，这是一种全球环境污染物，因燃烧煤炭而大量排放。我们研究了镍激活DNA损伤反应，并确定这种金属作为复制应激。基因毒性应激标记物表明ssDNA的积累和停滞的复制叉，镍处理的细胞依赖于ATR抑制DNA损伤和长期生存。复制压力由镍导致的不稳定的RRM 1和RRM 2的核糖核苷酸还原酶亚基和dNTPs的缺陷。Ni还增加了rNMP的DNA掺入（通过特异性荧光测定法检测），并由于TOP1-DNA蛋白交联（TOP1-DPC）的抑制修复而强烈增强了其遗传毒性。DPC陷阱试验发现，由于特定酶的下调，DNA交联的TOP 1的SUMO化和K48-聚泛素化严重受损。我们的研究结果将Ni确定为通过DNA嵌入的核糖核苷酸和TOP1-DPC蓄积诱导基因组不稳定性的人类致癌物，这是标准致突变性试验可检测性较差的致癌异常。镍的发现机制也可能在其他蛋白质反应性致癌物的遗传毒性中发挥作用。
Cancer is a genetic disease requiring multiple mutations for its development. However, many carcinogens are DNA-unreactive and nonmutagenic and consequently described as nongenotoxic. One of such carcinogens is nickel, a global environmental pollutant abundantly emitted by burning of coal. We investigated activation of DNA damage responses by Ni and identified this metal as a replication stressor. Genotoxic stress markers indicated the accumulation of ssDNA and stalled replication forks, and Ni-treated cells were dependent on ATR for suppression of DNA damage and long-term survival. Replication stress by Ni resulted from destabilization of RRM1 and RRM2 subunits of ribonucleotide reductase and the resulting deficiency in dNTPs. Ni also increased DNA incorporation of rNMPs (detected by a specific fluorescent assay) and strongly enhanced their genotoxicity as a result of repressed repair of TOP1-DNA protein crosslinks (TOP1-DPC). The DPC-trap assay found severely impaired SUMOylation and K48-polyubiquitination of DNA-crosslinked TOP1 due to downregulation of specific enzymes. Our findings identified Ni as the human carcinogen inducing genome instability via DNA-embedded ribonucleotides and accumulation of TOP1-DPC which are carcinogenic abnormalities with poor detectability by the standard mutagenicity tests. The discovered mechanisms for Ni could also play a role in genotoxicity of other protein-reactive carcinogens.
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影响因子：
3.3
作者：
Conover, Hailey N.;Lujan, Scott A.;Argueso, Juan Lucas
通讯作者：
Argueso, Juan Lucas
影响因子：
11.4
作者：
Huang, Shar-yin N.;Williams, Jessica S.;Pommier, Yves
通讯作者：
Pommier, Yves
DOI：
10.1084/jem.20120876
发表时间：
2012-07-30
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hiller B;Achleitner M;Glage S;Naumann R;Behrendt R;Roers A
通讯作者：
Roers A
影响因子：
4.5
作者：
Forslund, Josefin M. E.;Pfeiffer, Annika;Wanrooij, Sjoerd
通讯作者：
Wanrooij, Sjoerd
影响因子：
16
作者：
Ciccia A;Elledge SJ
通讯作者：
Elledge SJ