Feline XRCC4 undergoes rapid Ku-dependent recruitment to DNA damage sites.
Feline XRCC4 undergoes rapid Ku-dependent recruitment to DNA damage sites.
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猫XRCC4经历了KU依赖性募集到DNA损伤位点的快速募集。
DOI：
10.1002/2211-5463.13363
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发表时间：
2022-04
期刊：
影响因子：
2.6
通讯作者：
Koike A
中科院分区：
文献类型：
--
作者：
Koike M;Yutoku Y;Koike A
放疗和化疗耐药性仍然是人类和兽医癌症治疗中最大的挑战之一。XRCC4是非同源末端连接修复的重要分子，是放射增敏剂的一个有前途的靶点。XRCC 4的遗传变异和突变导致癌症易感性，XRCC 4也是人类小头原始侏儒症（MPD）的致病基因。开发临床有效的分子靶向药物需要准确了解XRCC4的功能和调控机制。本研究克隆了猫XRCC4基因的cDNA并进行了序列测定。比较分析表明，预测参与调节人XRCC4定位的序列和翻译后修饰位点，包括核定位信号，在猫XRCC4中大多是保守的。所有检测的负责人MPD的靶氨基酸在猫XRCC4中完全保守。此外，我们发现猫XRCC4的定位在细胞周期中动态变化。照射后不久，猫XRCC4在间期和有丝分裂期的激光诱导的DNA双链断裂（DSB）位点积累，这种积累依赖于Ku的存在。此外，XRCC4超家族蛋白XLF和PAXX在DSB位点积累。总的来说，这些发现表明，调节XRCC4时空定位的机制对人类和猫的XRCC4功能至关重要。我们的研究结果有助于阐明XRCC4的功能以及异常XRCC4在疾病中的作用，包括癌症和MPD，并可能有助于开发XRCC4靶向药物，如用于人类和猫的放射增敏剂。本研究克隆了猫XRCC4基因的cDNA并进行了分析。我们的数据表明，控制XRCC4时空定位的机制对XRCC4功能至关重要。我们的研究结果有助于阐明XRCC4的功能以及异常XRCC4在疾病中的作用，包括癌症和小头原始侏儒症，并可能有助于开发针对人类和猫的XRCC4靶向药物。
Radiation and chemotherapy resistance remain some of the greatest challenges in human and veterinary cancer therapies. XRCC4, an essential molecule for nonhomologous end joining repair, is a promising target for radiosensitizers. Genetic variants and mutations of XRCC4 contribute to cancer susceptibility, and XRCC4 is also the causative gene of microcephalic primordial dwarfism (MPD) in humans. The development of clinically effective molecular‐targeted drugs requires accurate understanding of the functions and regulatory mechanisms of XRCC4. In this study, we cloned and sequenced the cDNA of feline XRCC4. Comparative analysis indicated that sequences and post‐translational modification sites that are predicted to be involved in regulating the localization of human XRCC4, including the nuclear localization signal, are mostly conserved in feline XRCC4. All examined target amino acids responsible for human MPD are completely conserved in feline XRCC4. Furthermore, we found that the localization of feline XRCC4 dynamically changes during the cell cycle. Soon after irradiation, feline XRCC4 accumulated at laser‐induced DNA double‐strand break (DSB) sites in both the interphase and mitotic phase, and this accumulation was dependent on the presence of Ku. Additionally, XRCC4 superfamily proteins XLF and PAXX accumulated at the DSB sites. Collectively, these findings suggest that mechanisms regulating the spatiotemporal localization of XRCC4 are crucial for XRCC4 function in humans and cats. Our findings contribute to elucidating the functions of XRCC4 and the role of abnormal XRCC4 in diseases, including cancers and MPD, and may help in developing XRCC4‐targeted drugs, such as radiosensitizers, for humans and cats. In this study, feline XRCC4 cDNA was cloned and analyzed. Our data suggest that the mechanisms controlling the spatiotemporal localization of XRCC4 are critical for XRCC4 function. Our findings contribute to elucidating the XRCC4 functions and the role of abnormal XRCC4 in diseases, including cancers and microcephalic primordial dwarfism, and may help in developing XRCC4‐targeted drugs for humans and cats.
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XRCC4 的隐性变异使中国女性易患非 BRCA1/2 乳腺癌，并通过核定位失调损害 DNA 损伤反应
影响因子：
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作者：
He M;Hu X;Chen L;Cao AY;Yu KD;Shi TY;Kuang XY;Shi WB;Ling H;Li S;Qiao F;Yao L;Wei Q;Di GH;Shao ZM
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Shao ZM
DOI：
10.1006/bbrc.2000.3567
发表时间：
2000-10-05
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10.1016/j.bbrc.2011.07.032
发表时间：
2011-08-19
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3.1
作者：
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通讯作者：
Koike, Aki