Department of Chromosome Biology, Max Perutz Laboratories, University of Vienna, Vienna Biocenter, Vienna, Austria.
Expression Génétique Microbienne, UMR 8261, Centre Nationale de la Recherche Scientific, Université de Paris, Institut de Biologie Physico-Chimique, Paris, France.
J Cell Biol. 2021 Jun 7;220(6). doi: 10.1083/jcb.202012057.
An important quality control mechanism eliminates meiocytes that have experienced recombination failure during meiosis. The culling of defective oocytes in Caenorhabditis elegans meiosis resembles late oocyte elimination in female mammals. Here we show that topoisomerase 3 depletion generates DNA lesions in both germline mitotic and meiotic compartments that are less capable of triggering p53 (cep-1)-dependent apoptosis, despite the activation of DNA damage and apoptosis signaling. Elimination of nonhomologous, alternative end joining and single strand annealing repair factors (CKU-70, CKU-80, POLQ-1, and XPF-1) can alleviate the apoptosis block. Remarkably, the ability of single mutants in the other members of the Bloom helicase-topoisomerase-RMI1 complex to elicit apoptosis is not compromised, and depletion of Bloom helicase in topoisomerase 3 mutants restores an effective apoptotic response. Therefore, uncontrolled Bloom helicase activity seems to direct DNA repair toward normally not used repair pathways, and this counteracts efficient apoptosis. This implicates an as-yet undescribed requirement for topoisomerase 3 in mounting an effective apoptotic response to ensure germ cell quality control.
一种重要的质量控制机制消除了在减数分裂中经历重组失败的减数分裂细胞。在秀丽隐杆线虫减数分裂中，有缺陷的卵母细胞的剔除类似于雌性哺乳动物的晚期卵母细胞消除。在这里，我们表明拓扑异构酶 3 的耗竭会在生殖系有丝分裂和减数分裂区室中产生 DNA 损伤，尽管 DNA 损伤和细胞凋亡信号被激活，但这些损伤更不容易触发 p53（cep-1）依赖性细胞凋亡。非同源、替代末端连接和单链退火修复因子（CKU-70、CKU-80、POLQ-1 和 XPF-1）的消除可以减轻细胞凋亡的阻断。值得注意的是，Bloom 解旋酶-拓扑异构酶-RMI1 复合物中其他成员的单突变体引发细胞凋亡的能力没有受到影响，并且在拓扑异构酶 3 突变体中耗尽 Bloom 解旋酶可以恢复有效的细胞凋亡反应。因此，不受控制的 Bloom 解旋酶活性似乎将 DNA 修复导向通常不使用的修复途径，从而阻止了有效的细胞凋亡。这表明拓扑异构酶 3 对于引发有效的细胞凋亡反应以确保生殖细胞质量控制仍然存在未被描述的要求。
