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RNA m(6)A methylation regulates the ultraviolet-induced DNA damage response

机译：RNA m（6）A甲基化调节紫外线诱导的DNA损伤反应

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摘要

Cell proliferation and survival require the faithful maintenance and propagation of genetic information, which are threatened by the ubiquitous sources of DNA damage present intracellularly and in the external environment. A system of DNA repair, called the DNA damage response, detects and repairs damaged DNA and prevents cell division until the repair is complete. Here we report that methylation at the 6 position of adenosine (m(6)A) in RNA is rapidly (within 2 min) and transiently induced at DNA damage sites in response to ultraviolet irradiation. This modification occurs on numerous poly(A)+ transcripts and is regulated by the methyltransferase METTL3 (methyltransferase-like 3) 1 and the demethylase FTO (fat mass and obesity-associated protein) 2. In the absence of METTL3 catalytic activity, cells showed delayed repair of ultraviolet-induced cyclobutane pyrimidine adducts and elevated sensitivity to ultraviolet, demonstrating the importance of m(6)A in the ultraviolet-responsive DNA damage response. Multiple DNA polymerases are involved in the ultraviolet response, some of which resynthesize DNA after the lesion has been excised by the nucleotide excision repair pathway3, while others participate in trans-lesion synthesis to allow replication past damaged lesions in S phase(4). DNA polymerase. (Pol.), which has been implicated in both nucleotide excision repair and trans-lesion synthesis(5,6), required the catalytic activity of METTL3 for immediate localization to ultravioletinduced DNA damage sites. Importantly, Pol. overexpression qualitatively suppressed the cyclobutane pyrimidine removal defect associated with METTL3 loss. Thus, we have uncovered a novel function for RNA m(6)A modification in the ultraviolet-induced DNA damage response, and our findings collectively support a model in which m(6)A RNA serves as a beacon for the selective, rapid recruitment of Pol. to damage sites to facilitate repair and cell survival.
机译：细胞的增殖和存活需要对遗传信息的忠实维护和传播，而遗传信息受到细胞内和外部环境中普遍存在的DNA损伤的威胁。 DNA修复系统称为DNA损伤响应，可检测和修复受损的DNA，并在修复完成之前阻止细胞分裂。在这里我们报告说，在腺苷（m（6）A）在RNA的6个位置的甲基化是快速（2分钟内），并在DNA损伤部位响应紫外线辐射而被短暂诱导。这种修饰发生在许多poly（A）+转录物上，并受到甲基转移酶METTL3（甲基转移酶样3）1和脱甲基酶FTO（脂肪和肥胖相关蛋白）2的调节。在没有METTL3催化活性的情况下，细胞显示出延迟的紫外线诱导的环丁烷嘧啶加合物的修复和对紫外线的敏感性提高，表明m（6）A在紫外线响应DNA损伤反应中的重要性。紫外线反应涉及多种DNA聚合酶，其中一些在通过核苷酸切除修复途径切除病变后重新合成DNA3，而另一些参与跨病变合成以在S期复制通过受损的病变（4）。 DNA聚合酶。 （Pol。）已参与核苷酸切除修复和跨病变合成（5,6），需要METTL3的催化活性才能立即定位于紫外线诱导的DNA损伤位点。重要的是，Pol。过表达定性地抑制了与METTL3丢失相关的环丁烷嘧啶去除缺陷。因此，我们发现了紫外线诱导的DNA损伤反应中RNA m（6）A修饰的新功能，我们的发现共同支持了其中m（6）A RNA充当选择性，快速募集的信标的模型的损伤部位以促进修复和细胞存活。

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  • 来源
    《Nature》 |2017年第7646期|573-576|共4页
  • 作者

    Xiang Yang; Laurent Benoit; Hsu Chih-Hung; Nachtergaele Sigrid; Lu Zhike; Sheng Wanqiang; Xu Chuanyun; Hen Hao C.; Jian Ouyang; Wang Siqing; Ling Dominic; Hsu Pang-Hung; Zou Lee; Jambhekar Ashwini; IIe Chuan; Shi Yang;

  • 作者单位

    Boston Childrens Hosp, Dept Med, Div Newborn Med & Epigenet Program, Boston, MA 02115 USA|Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA;

    Boston Childrens Hosp, Dept Med, Div Newborn Med & Epigenet Program, Boston, MA 02115 USA|Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA;

    Boston Childrens Hosp, Dept Med, Div Newborn Med & Epigenet Program, Boston, MA 02115 USA|Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA;

    Univ Chicago, Dept Chem, Chicago, IL 60637 USA|Univ Chicago, Inst Biophys Dynam, 929 East 57th St, Chicago, IL 60637 USA|Univ Chicago, Howard Hughes Med Inst, 929 East 57th St, Chicago, IL 60637 USA;

    Univ Chicago, Dept Chem, Chicago, IL 60637 USA|Univ Chicago, Inst Biophys Dynam, 929 East 57th St, Chicago, IL 60637 USA|Univ Chicago, Howard Hughes Med Inst, 929 East 57th St, Chicago, IL 60637 USA;

    Boston Childrens Hosp, Dept Med, Div Newborn Med & Epigenet Program, Boston, MA 02115 USA|Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA;

    Boston Childrens Hosp, Dept Med, Div Newborn Med & Epigenet Program, Boston, MA 02115 USA|Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA;

    Boston Childrens Hosp, Dept Med, Div Newborn Med & Epigenet Program, Boston, MA 02115 USA|Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA;

    Harvard Med Sch, Massachusetts Gen Hosp Canc Ctr, Boston, MA 02109 USA|Harvard Med Sch, Massachusetts Gen Hosp Canc Ctr, Dept Pathol, Boston, MA 02109 USA;

    Boston Childrens Hosp, Dept Med, Div Newborn Med & Epigenet Program, Boston, MA 02115 USA|Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA|Fudan Univ, Inst Biomed Sci, Shanghai 200433, Peoples R China;

    Boston Childrens Hosp, Dept Med, Div Newborn Med & Epigenet Program, Boston, MA 02115 USA|Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA;

    Natl Taiwan Ocean Univ, Dept Biosci & Biotechnol, Keelung 202, Taiwan;

    Harvard Med Sch, Massachusetts Gen Hosp Canc Ctr, Boston, MA 02109 USA|Harvard Med Sch, Massachusetts Gen Hosp Canc Ctr, Dept Pathol, Boston, MA 02109 USA;

    Boston Childrens Hosp, Dept Med, Div Newborn Med & Epigenet Program, Boston, MA 02115 USA|Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA;

    Univ Chicago, Dept Chem, Chicago, IL 60637 USA|Univ Chicago, Inst Biophys Dynam, 929 East 57th St, Chicago, IL 60637 USA|Univ Chicago, Howard Hughes Med Inst, 929 East 57th St, Chicago, IL 60637 USA;

    Boston Childrens Hosp, Dept Med, Div Newborn Med & Epigenet Program, Boston, MA 02115 USA|Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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