Zygotic Genome Activation Triggers Chromosome Damage and Checkpoint Signaling in C. elegans Primordial Germ Cells

Abstract

Recent findings have identified highly transcribed genes as a source of genome instability; however, the degree to which large-scale shifts in transcriptional activity cause DNA damage was not known. One example of a large-scale shift in transcriptional activity occurs during development, when maternal regulators are destroyed and zygotic genome activation (ZGA) occurs. Here, we show that ZGA triggers widespread chromosome damage in the primordial germ cells of the nematode C. elegans. We show that ZGA-induced DNA damage activates a checkpoint response, the damage is repaired by factors required for inter-sister homologous recombination, and topoisomerase II plays a role in generating the damage. These findings identify ZGA as a source of intrinsic genome instability in the germline and suggest that genome destabilization may be a general consequence of extreme shifts in cellular transcriptional load.

Trouble in transitioning: activation of zygotic transcription can lead to DNA breakage and genome instability

“…1). 5 Interestingly, we also noticed that Z2 and Z3 did not divide synchronously, rather either Z2 or Z3 would divide first, and the other would follow after another 2 or so hours. The basis for this asynchrony in cell cycle reentry is not known.…”

“…We opted to pursue the basis for the sterility phenotype, and observed that chk-1(RNAi) adults showed a complete absence of a germline. 5 When we looked earlier in development, we saw that unfed chk-1 (RNAi) L1s had a superficially normal primordial gonad, where Z2/Z3 were arrested at G2/prophase, as inferred by a measured 4N DNA content. 5 This implied that the chk-1(RNAi) sterility phenotype was manifested sometime between the L1 stage and adulthood.…”

“…5 When we looked earlier in development, we saw that unfed chk-1 (RNAi) L1s had a superficially normal primordial gonad, where Z2/Z3 were arrested at G2/prophase, as inferred by a measured 4N DNA content. 5 This implied that the chk-1(RNAi) sterility phenotype was manifested sometime between the L1 stage and adulthood. We next carefully examined the fate of Z2/Z3 after the nutrient-dependent release from cell cycle arrest at the L1 stage, and the results were very surprising indeed.…”

“…Recent work from our laboratory has shed light on this, with the surprising finding that transcription-induced DNA damage occurs on a wide scale during germline activation in C. elegans. 5 polymerase II (RNAPII)-based gene transcription. 6,7 During embryogenesis, P lineage cells give rise to 2 division products, one a somatic lineage precursor, and the other a somatic and germline precursor.…”

A twist of fate: How a meiotic protein is providing new perspectives on germ cell development

“…These events are associated with a spike in transcription-coupled DNA damage that needs to be repaired for proper division to ensue. 23 In light of these studies, it is intriguing to speculate that xnd-1 or nos-1/2 may alter DNA damage repair in the L1 larvae leading to PGC loss and/or reduced proliferation. In support of this hypothesis, xnd-1 mutants are hypersensitive to gamma irradiation and the brood size defects of xnd-1 are partially suppressed by mutations in the checkpoint kinase, atm-1 (McClendon and Yanowitz, submitted).…”