Hot spots of DNA double-strand breaks in human rDNA units are produced in vivo

Abstract

Endogenous hot spots of DNA double-strand breaks (DSBs) are tightly linked with transcription patterns and cancer genomics1,2. There are nine hot spots of DSBs located in human rDNA units3–6. Here we describe that the profiles of these hot spots coincide with the profiles of γ-H2AX or H2AX, strongly suggesting a high level of in vivo breakage inside rDNA genes. The data were confirmed by microscopic observation of the largest γ-H2AX foci inside nucleoli in interphase chromosomes. In metaphase chromosomes, we observed that only some portion of rDNA clusters possess γ-H2AX foci and that all γ-H2AX foci co-localize with UBF-1 binding sites, which strongly suggests that only active rDNA units possess the hot spots of DSBs. Both γ-H2AX and UBF-1 are epigenetically inherited and thus indicate the rDNA units that were active in the previous cell cycle. These results have implications for diverse fields, including epigenetics and cancer genomics.

The epigenetic regulator SIRT7 guards against mammalian cellular senescence induced by ribosomal DNA instability

“…Moreover, rDNA sequences are thought to be the most fragile part of the genome in both yeast and mammalian cells (11,14). In addition to being a hot spot for translocations in human cancers, recent work indicates that rDNA sequences are hot spots for phosphorylated ␥-H2AX, a chromatin marker of DNA DSBs (40). These DSB hot spots colocalize with signs of active transcription, consistent with the model that an open chromatin state may be permissive for rDNA damage.…”

Ribosomal biogenesis as an emerging target of neurodevelopmental pathologies

“…In addition, hyperactive UBTF1 could lead to rDNA loci loss and/or a neurotoxic DNA damage response as increased rRNA transcription is associated with rDNA DSBs, recombinational instability of rDNA and rDNA damage (Kobayashi and Ganley ; Tchurikov et al . ; Xie et al . ).…”

Modifications of expression of genes and proteins involved in DNA repair and nitric oxide metabolism by carbatonides [disodium-2,6-dimethyl-1,4-dihydropyridine- 3,5-bis(carbonyloxyacetate) derivatives] in intact and diabetic rats

“…It is phosphorylated by kinases such as ataxia telangiectasia mutated and ataxia telangiectasia mutated-Rad3-related in the PI3K pathway (38). However, we did observe an increased expression of the gene in blood cells, coherent with DNA breakage increase; perhaps, this reflects the fact that in lymphocytes the non-phosphorylated form of histone is also translocated to DNA breakage foci (39) triggering an increased transcription of the gene by feedback mechanism. Etcarbatone up-regulated also H2AX histone in myocardium.…”