RNA-mediated double-strand break repair in human cells

Double-strand breaks (DSBs) in DNA are challenging lesions to repair. Human cells employ at least three DSB repair mechanisms, with a preference for non-homologous end joining (NHEJ) over homologous recombination (HR) and microhomology-mediated end joining (MMEJ)1,2. In contrast to HR, NHEJ and MMEJ do not utilize a DNA template molecule to recover damaged and/or lost nucleotides2. NHEJ directly ligates broken DNA ends, while MMEJ exploits the alignment of short microhomologies on the DSB sides and is associated with deletions of the sequence between the microhomologies3,4. It is unknown whether and to what extent a transcript RNA has a direct role in DSB-repair mechanisms in mammalian cells. Here, we show that both coding and non-coding transcript RNA facilitates DSB repair in a sequence-specific manner in human cells. Depending on its sequence complementarity with the broken DNA ends, the transcript RNA could promote the repair of a DSB or gap in its DNA gene via NHEJ or MMEJ, or mediate RNA-templated repair. The transcript RNA influences DSB repair by NHEJ and MMEJ even when the transcription level is low. The results demonstrate an unexpected role of transcript RNA in directing the way DSBs are repaired in human cells and maintaining genome stability.