ADARp150 可以抵消全基因组复制。
ADARp150 counteracts whole genome duplication.
发表日期：2024 Aug 27
作者：
Frank van Gemert, Alexandra Drakaki, Isabel Morales Lozano, Daniël de Groot, Maud Schoot Uiterkamp, Natalie Proost, Cor Lieftink, Marieke van de Ven, Roderick L Beijersbergen, Heinz Jacobs, Hein Te Riele
来源：
NUCLEIC ACIDS RESEARCH
摘要：
G1/S 检查点的控制受损会在不允许的条件下启动 DNA 复制。计划外的 S 期进入与 DNA 复制应激有关，需要其他检查点或细胞途径来维持增殖。在这里，我们发现了 ADARp150 在生长限制条件下维持 G1/S 检查点缺陷细胞增殖的必要条件。除了其在反向短散布核元件 (SINE) 中成熟的 mRNA 编辑功能外，我们发现 ADARp150 在有丝分裂中发挥着关键功能。 ADARp150 耗竭导致四倍体化，在丝裂原缺乏的条件下阻碍细胞增殖。从机制上讲，我们表明 ADAR1 缺失会诱导 Cyclin B3 的异常表达，这是有丝分裂失败和全基因组复制的原因。最后，我们发现体内 ADAR1 耗竭引起的四倍体化也会阻碍肿瘤生长。© 作者 2024。由牛津大学出版社代表 Nucleic Acids Research 出版。
Impaired control of the G1/S checkpoint allows initiation of DNA replication under non-permissive conditions. Unscheduled S-phase entry is associated with DNA replication stress, demanding for other checkpoints or cellular pathways to maintain proliferation. Here, we uncovered a requirement for ADARp150 to sustain proliferation of G1/S-checkpoint-defective cells under growth-restricting conditions. Besides its well-established mRNA editing function in inversely oriented short interspersed nuclear elements (SINEs), we found ADARp150 to exert a critical function in mitosis. ADARp150 depletion resulted in tetraploidization, impeding cell proliferation in mitogen-deprived conditions. Mechanistically we show that ADAR1 depletion induced aberrant expression of Cyclin B3, which was causative for mitotic failure and whole-genome duplication. Finally, we find that also in vivo ADAR1-depletion-provoked tetraploidization hampers tumor outgrowth.© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.