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

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.

Automated summary

The importance of long non-coding RNAs (lncRNAs) in various areas, including tumor biology, is unquestionable based on the flurry of publications dedicated to their functions in the last decade. However, their contribution to the early stages of oncogenesis is still poorly understood. In this study, we discovered a new role for lncRNAs in stimulating specific chromosomal rearrangements in response to DNA damage. Specifically, we demonstrated that lncRNA CASTL1 (ENSG00000269945) promotes the formation of the CCDC6-RET inversion (RET/PTC1) in human thyroid cells exposed to radiation or chemical DNA damage. The findings suggest a new avenue for studying early oncogenesis in various tumor types, particularly those associated with DNA damage.