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Abstract:
Stem and progenitor cells undergo a global elevation of nascent transcription, or hyper-
transcription, during key developmental transitions involving rapid cell proliferation. The
chromatin remodeler Chd1 mediates hypertranscription in pluripotent cells but its mechanism
of action remains poorly understood. Here we report a novel role for Chd1 in protecting
genome integrity at promoter regions by preventing DNA double-stranded break (DSB)
accumulation in ES cells. Chd1 interacts with several DNA repair factors including Atm, Parp1,
Kap1 and Topoisomerase 2βand its absence leads to an accumulation of DSBs at Chd1-bound
Pol II-transcribed genes and rDNA. Genes prone to DNA breaks in Chd1 KO ES cells are
longer genes with GC-rich promoters, a more labile nucleosomal structure and roles in
chromatin regulation, transcription and signaling. These results reveal a vulnerability of
hypertranscribing stem cells to accumulation of endogenous DNA breaks, with important
implications for developmental and cancer biology.
