RECQL5 KIX domain splicing isoforms have distinct functions in transcription repression and DNA damage response

Abstract

RecQL5, a mammalian RecQ family protein, is involved in the regulation of transcription elongation, DNA damage response, and DNA replication. Here, we identified and characterized an alternative splicing isoform of RECQL5 (RECQL5 beta 1), which contains 17 additional amino acid residues within the RECQL5 KIX domain when compared with the canonical isoform (RECQL5 beta). RECQL5 beta 1 had a markedly decreased binding affinity to RNA polymerase II (Pol II) and poorly competed with the transcription elongation factor TFIIS for binding to Pol II. As a result, this isoform has a weaker activity for repression of transcription elongation. In contrast, we discovered that RECQL5 beta 1 could bind stronger to MRE11, which is a primary sensor of DNA double-strand breaks (DSBs). Furthermore, we found that RECQL5 beta 1 promoted DNA repair in the RECQL5 beta 1 rescue cells. These results suggest that RECQL5 beta mainly functions as a transcription repressor, while the newly discovered RECQL5 beta 1 has a specialized role in DNA damage response. Taken together, our data suggest a cellular-functional specialization for each KIX splicing isoform in the cell.