Loss of the N-terminal methyltransferase NRMT1 increases sensitivity to DNA damage and promotes mammary oncogenesis.
Loss of the N-terminal methyltransferase NRMT1 increases sensitivity to DNA damage and promotes mammary oncogenesis.
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DOI：
10.18632/oncotarget.3653
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发表时间：
2015-05-20
期刊：
影响因子：
--
通讯作者：
Schaner Tooley CE
中科院分区：
文献类型：
--
作者：
Bonsignore LA;Butler JS;Klinge CM;Schaner Tooley CE
尽管在四十多年前就发现了n端甲基化的功能，但它在很大程度上仍然是一个谜。我们发现了第一个哺乳动物n端甲基转移酶NRMT1，从而发现了n端甲基化的许多新功能，包括DNA/蛋白质相互作用的调节，精确的有丝分裂和核苷酸切除修复（NER）。在这里，我们测试了NRMT1是否对DNA双链断裂（DSB）修复也很重要，并考虑到它在细胞周期调节和DNA损伤反应中的已知作用，分析了NRMT1是否作为肿瘤抑制因子。我们发现，NRMT1敲低显著增强乳腺癌细胞系对依托泊苷治疗和γ辐射的敏感性，并增加增殖率、侵袭电位、非锚定生长、异种移植物肿瘤大小和他莫昔芬敏感性。有趣的是，这将NRMT1定位为参与多种DNA修复途径的肿瘤抑制蛋白，并表明，与BRCA1和BRCA2类似，NRMT1的缺失可能导致肿瘤对多种DNA损伤化疗药物的敏感性增强。
Though discovered over four decades ago, the function of N-terminal methylation has mostly remained a mystery. Our discovery of the first mammalian N-terminal methyltransferase, NRMT1, has led to the discovery of many new functions for N-terminal methylation, including regulation of DNA/protein interactions, accurate mitotic division, and nucleotide excision repair (NER). Here we test whether NRMT1 is also important for DNA double-strand break (DSB) repair, and given its previously known roles in cell cycle regulation and the DNA damage response, assay if NRMT1 is acting as a tumor suppressor. We find that NRMT1 knockdown significantly enhances the sensitivity of breast cancer cell lines to both etoposide treatment and γ-irradiation, as well as, increases proliferation rate, invasive potential, anchorage-independent growth, xenograft tumor size, and tamoxifen sensitivity. Interestingly, this positions NRMT1 as a tumor suppressor protein involved in multiple DNA repair pathways, and indicates, similar to BRCA1 and BRCA2, its loss may result in tumors with enhanced sensitivity to diverse DNA damaging chemotherapeutics.
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影响因子：
37.3
作者：
Amato A;Schillaci T;Lentini L;Di Leonardo A
通讯作者：
Di Leonardo A
影响因子：
3.8
作者：
Bostelman, Lindsey J.;Keller, Andrew M.;Thompson, Jeffrey S.
通讯作者：
Thompson, Jeffrey S.
DOI：
10.1073/pnas.1403737111
发表时间：
2014-08-05
影响因子：
11.1
作者：
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通讯作者：
La Thangue, Nicholas B.
影响因子：
3.8
作者：
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通讯作者：
Saunders, Philippa T. K.
影响因子：
6.4
作者：
Ibrahim, Sherif A.;Yip, George W.;Goette, Martin
通讯作者：
Goette, Martin