State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, 100871 Beijing, China; Beijing Advanced Center of RNA Biology (BEACON), Peking University, Beijing, China.
MOE Key Laboratory of Bioinformatics, Center for Synthetic & Systems Biology, School of Life Sciences, Joint Graduate Program of Peking-Tsinghua-National Institute of Biological Science, Tsinghua University, 100084 Beijing, China.
Cell. 2024 Oct 17;187(21):6035-6054.e27. doi: 10.1016/j.cell.2024.08.040. Epub 2024 Sep 20.
mA modification is best known for its critical role in controlling multiple post-transcriptional processes of the mRNAs. Here, we discovered elevated levels of mA modification on centromeric RNA (cenRNA) in cancerous cells compared with non-cancerous cells. We then identified CENPA, an H3 variant, as an mA reader of cenRNA. CENPA is localized at centromeres and is essential in preserving centromere integrity and function during mitosis. The mA-modified cenRNA stabilizes centromeric localization of CENPA in cancer cells during the S phase of the cell cycle. Mutations of CENPA at the Leu61 and the Arg63 or removal of cenRNA mA modification lead to loss of centromere-bound CENPA during S phase. This in turn results in compromised centromere integrity and abnormal chromosome separation and hinders cancer cell proliferation and tumor growth. Our findings unveil an mA reading mechanism by CENPA that epigenetically governs centromere integrity in cancer cells, providing potential targets for cancer therapy.
mA 修饰以其在控制 mRNA 的多个转录后过程中的关键作用而闻名。在这里，我们发现与非癌细胞相比，癌细胞中端粒 RNA（cenRNA）上的 mA 修饰水平升高。然后，我们鉴定出 H3 变体 CENPA 是 cenRNA 的 mA 阅读器。CENPA 定位于着丝粒，在有丝分裂过程中对于维持着丝粒的完整性和功能至关重要。mA 修饰的 cenRNA 在细胞周期的 S 期稳定了癌细胞中 CENPA 的着丝粒定位。CENPA 的 Leu61 和 Arg63 突变或 cenRNA mA 修饰的缺失导致 S 期失去着丝粒结合的 CENPA。这反过来又导致着丝粒完整性受损，染色体分离异常，阻碍癌细胞增殖和肿瘤生长。我们的研究结果揭示了 CENPA 通过 mA 阅读机制来表观遗传调控癌细胞中着丝粒的完整性，为癌症治疗提供了潜在的靶点。
