Factors That Affect the Formation of Chromosomal Translocations in Cells

Abstract

Chromosomal translocations are products of the illegitimate repair of DNA double-strand breaks (DSBs). Their formation can bring about significant structural and molecular changes in the cell that can be physiologically and pathologically relevant. The induced changes may lead to serious and life-threatening diseases such as cancer. As a growing body of evidence suggests, the formation of chromosomal translocation is not only affected by the mere close spatial proximity of gene loci as potential translocation partners. Several factors may affect formation of chromosomal translocations, including chromatin motion to the potential sources of DSBs in the cell. While these can be apparently random events, certain chromosomal translocations appear to be cell-type-specific. In this review, we discuss how chromosomal translocations are formed and explore how different cellular factors contribute to their formation.

lncRNA: A new danger for genome integrity

“…Chromosomal rearrangements result from DNA breaks and erroneous DNA repair; their appearance is a risk factor for oncogenic cell transformation 2 . Common threats for chromosomal rearrangements originate from the cellular machinery itself, which comprises DNA‐damaging cellular activities (replication stress and reactive oxygen species), programmed DNA‐cutting enzymes (e.g., recombination‐activating gene (RAG) 1/2 complex or activation‐induced deaminase (AID) indispensable for proper antibody production in B cells), specific genome architecture and stochastic DNA movements that allow DNA breaks clustering, and, finally, error‐prone DNA repair activities 2 . Another player in the genesis of chromosomal rearrangements could be microhomology in the DNA of the partners involved in a chromosomal translocation, inversion or deletion 3 …”

“…2 Common threats for chromosomal rearrangements originate from the cellular machinery itself, which comprises DNA-damaging cellular activities (replication stress and reactive oxygen species), programmed DNA-cutting enzymes (e.g., recombination-activating gene (RAG) 1/2 complex or activation-induced deaminase (AID) indispensable for proper antibody production in B cells), specific genome architecture and stochastic DNA movements that allow DNA breaks clustering, and, finally, error-prone DNA repair activities. 2 Another player in the genesis of chromosomal rearrangements could be microhomology in the DNA of the partners involved in a chromosomal translocation, inversion or deletion. 3 These factors render the cell intrinsically vulnerable to spontaneous chromosomal rearrangements.…”

Epstein−Barr virus reactivation induces MYC‐IGH spatial proximity and t(8;14) in B cells

“…To be generated, a translocation requires simultaneous DNA double strand breaks (DSBs) on the two partner chromosomes, DSB repair through the error-prone nonhomologous end-joining (NHEJ) pathway and the spatial proximity between the two partners. [21][22][23][24] The activation-induced deaminase (AID), implicated in somatic hypermutation and class switch recombination in B cells in the germinal center of lymph nodes, is the primary source of DSBs in the MYC and IGH loci. [25][26][27] The IGH rearrangements are required to produce specific affine antibodies, but they also incidentally predispose to t (8;14).…”

Specificity of cancer-related chromosomal translocations is linked to proximity after the DNA double-strand break and subsequent selection

“…Cell-specific traits that may potentially affect translocation formation include preferential occurrence of DSBs at specific loci in specific cell types [e.g. due to chromatin state or the activity of intrinsic DNA-cutting enzymes ( 9 , 11 )] and/or predetermined factors that affect DNA repair [e.g. transcriptional activity, loci spatial proximity, the activity of specific repair factors or even cell-specific expression of chromosomal aberrations stimulating long noncoding RNAs (lncRNAs) ( 12 )].…”

“…While previous studies have extensively explored the occurrence of cell-specific DSBs, less is known about the risk factors that interfere with translocation-prone DSB repair once they are already formed in a particular cell type. Chromatin state, DSB movement and DNA damage sensing and repair mechanisms influence the generation of chromosomal translocations at this step ( 9 ). The presence of specific transcripts [e.g.…”