Adversary of DNA integrity: A long non‐coding RNA stimulates driver oncogenic chromosomal rearrangement in human thyroid cells

Abstract

The flurry of publications devoted to the functions of long non‐coding RNAs (lncRNAs) published in the last decade leaves no doubt about the exceptional importance of lncRNAs in various areas including tumor biology. However, contribution of lncRNAs to the early stages of oncogenesis remains poorly understood. In this study we explored a new role for lncRNAs: stimulation of specific chromosomal rearrangements upon DNA damage. We demonstrated that lncRNA CASTL1 (ENSG00000269945) stimulates the formation of the CCDC6‐RET inversion (RET/PTC1) in human thyroid cells subjected to radiation or chemical DNA damage. Facilitation of chromosomal rearrangement requires lncRNA to contain regions complementary to the introns of both CCDC6 and RET genes as deletion of these regions deprives CASTL1 of the ability to stimulate the gene fusion. We found that CASTL1 expression is elevated in tumors with CCDC6‐RET fusion which is the most frequent rearrangement in papillary thyroid carcinoma. Our results open a new venue for the studies of early oncogenesis in various tumor types, especially those associated with physical or chemical DNA damage.

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

“…The presence of specific transcripts [e.g. lncRNAs that share homology regions for two different loci ( 12 , 13 )] or certain drugs ( 14 ) can also affect the formation of chromosomal rearrangements. Understanding these risk factors is crucial for developing targeted interventions to prevent the occurrence of translocations and the development of related diseases such as cancer.…”

lncRNA: A new danger for genome integrity

“…In this issue of the International Journal of Cancer, Demin et al 1 describe a long noncoding RNA CASTL (chromosomal aberrations stimulating lncRNA) that facilitates CCDC6-RET fusion (inv(10)(q11; q21)). Expression of CASTL1 is cell-type specific and can account for the appearance of CCDC6-RET fusion only in specific cell types.…”