HSF1 and YTHDC1 facilitate DNA damage repair upon heat stress by promoting the expressions of repair related genes

External stressors, especially heat stress, always lead to DNA damage and genome instability in cells. However, how cells rapidly response to these DNA damage remains largely unknown. In this study, we found that the major transcription factor in heat shock response, HSF1, activated several NHEJ pathway related genes, especially NHEJ1, through the puncta it formed, thereby promoting the NHEJ pathway, reducing the DNA double-strand break upon heat stress. Furthermore, RNA m6A modification and its reader YTHDC1 were also found to play a role in this process, promoting the splicing of the NHEJ1 gene. Depletion of HSF1 or YTHDC1 led to increased nuclear γH2AX intensities in the heat shocked cells, which was rescued by overexpression of NHEJ1. Besides, overexpression of HSF1 or YTHDC1 both caused increased NHEJ pathway level in the heat shocked cells, indicating the HSF1/YTHDC1 – NHEJ1 – DNA double-strand repair axis. Our findings investigate an approach through which cells repair their damaged DNAs in the heat shock response, offering a new insight of how cells maintain a bare-minimum genome stability when exposed to external stressors.