DNA damage causes cancer, impairs development and accelerates aging. Transcription-blocking lesions and transcription-coupled repair defects lead to developmental failure and premature aging in humans. Following DNA repair, homeostatic processes need to be reestablished to ensure development and maintain tissue functionality. Here, we report that, in Caenorhabditis elegans, removal of the WRAD complex of the MLL/COMPASS H3K4 methyltransferase exacerbates developmental growth retardation and accelerates aging, while depletion of the H3K4 demethylases SPR-5 and AMX-1 promotes developmental growth and extends lifespan amid ultraviolet-induced damage. We demonstrate that DNA-damage-induced H3K4me2 is associated with the activation of genes regulating RNA transport, splicing, ribosome biogenesis and protein homeostasis and regulates the recovery of protein biosynthesis that ensures survival following genotoxic stress. Our study uncovers a role for H3K4me2 in coordinating the recovery of protein biosynthesis and homeostasis required for developmental growth and longevity after DNA damage.

DNA 损伤会导致癌症、损害发育并加速衰老。转录阻断损伤和转录偶联修复缺陷导致人类发育失败和过早衰老。DNA 修复后，需要重新建立稳态过程以确保发育和维持组织功能。在这里，我们报告说，在秀丽隐杆线虫中，去除 MLL/COMPASS H3K4 甲基转移酶的 WRAD 复合物会加剧发育生长迟缓并加速衰老，而 H3K4 去甲基化酶 SPR-5 和 AMX-1 的消耗促进发育生长并在紫外线诱导的损伤中延长寿命。我们证明 DNA 损伤诱导的 H3K4me2 与调节 RNA 转运、剪接、核糖体生物合成和蛋白质稳态的基因的激活有关，并调节蛋白质生物合成的恢复，确保基因毒性应激后的存活。我们的研究揭示了 H3K4me2 在协调蛋白质生物合成恢复和 DNA 损伤后发育生长和寿命所需的稳态方面的作用。