Solar-UV-signature mutation prefers TCG to CCG: extrapolative consideration from UVA1-induced mutation spectra in mouse skin
Solar-UV-signature mutation prefers TCG to CCG: extrapolative consideration from UVA1-induced mutation spectra in mouse skin
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DOI：
10.1039/c3pp25444e
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发表时间：
2013-01-01
影响因子：
3.1
通讯作者：
Morita, Akimichi
中科院分区：
文献类型：
--
作者：
Ikehata, Hironobu;Kumagai, Jun;Morita, Akimichi
UVA 1通过在DNA中产生环丁烷嘧啶二聚体（CPD）并优先诱导日光-UV-特征突变、甲基化CpG相关二嘧啶（Py-mCpG）位点的C -> T碱基取代突变对哺乳动物皮肤施加其遗传毒性，如先前使用364 nm激光作为UVA 1源和利用转基因作为突变报告基因的lacZ转基因小鼠所证明的。在本研究中，我们证实了宽带UVA 1源在小鼠表皮中诱导了与UVA 1激光相同的突变谱，将先前的结果从单一的364 nm推广到更宽的UVA 1波长范围（340-400 nm）。结合我们以前的数据在小鼠表皮的突变光谱由UVB，UVA 2和太阳紫外线辐射，我们证明了太阳紫外线的签名突变是常见的波长范围从UVB到UVA，并发现UVA 1诱导这种突变更优先于其他较短的波长范围。这一发现表明，已知偏好Py-mCpG位点的太阳能UV特征突变引起的CPD可以用UVR的较长波长区域提供的能量产生，这表明通过将嘧啶碱基激发到能量状态的光化学反应可以通过吸收甚至低能量的UVR来实现。另一方面，在UVB和太阳UVR的突变光谱中观察到的太阳UV特征突变的比例较低，表明通过嘧啶碱基的激发单线态的直接光化学反应，这只能通过高能UVR来完成，也参与了在UVR的较短波长处的突变诱导。我们还发现，太阳-UV特征偏好5 '-TCG-3'至5 '-CCG-3'作为突变靶位点，这与UVA选择性地在含胸腺嘧啶的二嘧啶位点诱导CPD以及太阳UVR优选地在Py-mCpG位点诱导CPD的事实一致。然而，来自非黑色素瘤皮肤癌的人p53基因的突变谱显示对5 '-CCG-3'位点的相反偏好。这种位点偏好的明显差异似乎是由于缺乏人类p53基因非转录链上可突变为错义突变的5 '-TCG-3'位点，而这应该是在来自太阳的选择压力下进化获得的。
UVA1 exerts its genotoxicity on mammalian skin by producing cyclobutane pyrimidine dimers (CPDs) in DNA and preferentially inducing solar-UV-signature mutations, C -> T base substitution mutations at methylated CpG-associated dipyrimidine (Py-mCpG) sites, as demonstrated previously using a 364 nm laser as a UVA1 source and lacZ-transgenic mice that utilize the transgene as a mutational reporter. In the present study, we confirmed that a broadband UVA1 source induced the same mutation profiles in mouse epidermis as the UVA1 laser, generalizing the previous result from a single 364 nm to a wider wavelength range of UVA1 (340-400 nm). Combined with our previous data on the mutation spectra induced in mouse epidermis by UVB, UVA2 and solar UVR, we proved that the solar-UV-signature mutation is commonly observed in the wavelength range from UVB to UVA, and found that UVA1 induces this mutation more preferentially than the other shorter wavelength ranges. This finding indicates that the solar-UV-signature mutation-causing CPDs, which are known to prefer Py-mCpG sites, could be produced with the energy provided by the longer wavelength region of UVR, suggesting a photochemical reaction through the excitation of pyrimidine bases to energy states that can be accomplished by absorption of even low-energy UVR. On the other hand, the lower proportions of solar-UV-signature mutations observed in the mutation spectra for UVB and solar UVR indicate that the direct photochemical reaction through excited singlet state of pyrimidine bases, which can be accomplished only by high-energy UVR, is also involved in the mutation induction at those shorter wavelengths of UVR. We also found that the solar-UV signature prefers 5'-TCG-3' to 5'-CCG-3' as mutational target sites, consistent with the fact that UVA induces CPDs selectively at thymine-containing dipyrimidine sites and that solar UVR induces them preferably at Py-mCpG sites. However, the mutation spectrum in human p53 gene from non-melanoma skin cancers shows the opposite preference for 5'-CCG-3' sites. This apparent discrepancy in the site preference seems to result from the lack of 5'-TCG-3' sites mutable to missense mutations on the nontranscribed strand of human p53 gene, which should be evolutionally acquired under selective pressure from the sun.