Chromosomal Translocations in NK-Cell Lymphomas Originate from Inter-Chromosomal Contacts of Active rDNA Clusters Possessing Hot Spots of DSBs.

Abstract

Simple SummaryThere are nine DSB hot spots located in the non-transcribed spacer of human rDNA units. Circular chromosome conformation capture data indicate that the rDNA clusters often shape contact with a specific set of chromosomal regions containing genes controlling differentiation and cancer, and often possessing the DSB hot spots. The data suggest a mechanism for rDNA-mediated translocation, and some of them could lead to tumorigenesis. Here, we searched for translocations in which rDNA clusters are involved. WGS data of normal T cells and NK-cell lymphomas from the same individuals were used. We revealed numerous translocations in which rDNA units are involved. The sites of these translocations in normal T cells and in the lymphomas were mostly different, but occurred at about the same frequency in both cell types. We conclude that oncogenic translocations lead to dysregulation of a specific set of genes controlling development.Endogenous hot spots of DNA double-strand breaks (DSBs) are tightly linked with transcription patterns and cancer. There are nine hot spots of DSBs (denoted Pleiades) in human rDNA units that are located exclusively inside the intergenic spacer (IGS). Profiles of Pleiades coincide with the profiles of γ-H2AX, 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. Circular chromosome conformation capture (4C) data indicate that the rDNA units often make contact with a specific set of chromosomal regions containing genes that are involved in differentiation and cancer. Interestingly, these regions also often possess hot spots of DSBs that provide the potential for Robertsonian and oncogenic translocations. In this study, we searched for translocations in which rDNA clusters are involved. The whole genome sequence (WGS) data of normal T cells and NK-cell lymphomas from the same individuals revealed numerous translocations in which Pleiades were involved. The sites of these translocations in normal T cells and in the lymphomas were mostly different, although there were also some common sites. The genes at translocations in normal cells and in lymphomas are associated with predominantly non-overlapping lists of genes that are depleted with silenced genes. Our data indicate that rDNA-mediated translocations occur at about the same frequency in the normal T cells and NK-lymphoma cells but differ at particular sites that correspond to open chromatin. We conclude that oncogenic translocations lead to dysregulation of a specific set of genes controlling development. In normal T cells and in NK cells, there are hot spots of translocations at sites possessing strong H3K27ac marks. The data indicate that Pleiades are involved in rDNA-mediated translocation.