Department of Geriatrics, Medical center on Aging of Shanghai Ruijin Hospital, Shanghai Jiaotong University school of Medicine; International Laboratory in Hematology and Cancer, Shanghai Jiao Tong University School of Medicine/Ruijin Hospital/CNRS/Inserm/Côte d'Azur University, PR China.
Côte d'Azur University, CNRS, INSERM, IRCAN, Faculty of Medicine Nice, France.
Nucleic Acids Res. 2022 Feb 28;50(4):2081-2095. doi: 10.1093/nar/gkac065.
The shelterin protein complex is required for telomere protection in various eukaryotic organisms. In mammals, the shelterin subunit TRF2 is specialized in preventing ATM activation at telomeres and chromosome end fusion in somatic cells. Here, we demonstrate that the zebrafish ortholog of TRF2 (encoded by the terfa gene) is protecting against unwanted ATM activation genome-wide. The terfa-compromised fish develop a prominent and specific embryonic neurodevelopmental failure. The heterozygous fish survive to adulthood but exhibit a premature aging phenotype. The recovery from embryonic neurodevelopmental failure requires both ATM inhibition and transcriptional complementation of neural genes. Furthermore, restoring the expression of TRF2 in glial cells rescues the embryonic neurodevelopment phenotype. These results indicate that the shelterin subunit TRF2 evolved in zebrafish as a general factor of genome maintenance and transcriptional regulation that is required for proper neurodevelopment and normal aging. These findings uncover how TRF2 links development to aging by separate functions in gene expression regulation and genome stability control.
庇护体蛋白复合物是各种真核生物保护端粒所必需的。在哺乳动物中，庇护体亚基 TRF2 专门用于防止 ATM 在端粒处的激活和体细胞中染色体末端融合。在这里，我们证明了 TRF2 的斑马鱼同源物（由 terfa 基因编码）在全基因组范围内防止了不必要的 ATM 激活。terfa 缺陷的鱼会出现明显而特异的胚胎神经发育失败。杂合子鱼能存活到成年，但表现出早衰表型。从胚胎神经发育失败中恢复需要 ATM 抑制和神经基因的转录补救。此外，恢复神经胶质细胞中 TRF2 的表达可以挽救胚胎神经发育表型。这些结果表明，庇护体亚基 TRF2 在斑马鱼中进化为基因组维持和转录调控的一般因子，这对于正常的神经发育和正常衰老都是必需的。这些发现揭示了 TRF2 如何通过在基因表达调控和基因组稳定性控制中的不同功能将发育与衰老联系起来。
