RT Journal Article
SR Electronic
T1 Chd1 regulates repair of promoter-proximal DNA breaks to sustain hypertranscription in embryonic stem cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 659995
DO 10.1101/659995
A1 Aydan Bulut-Karslioglu
A1 Hu Jin
A1 Marcela Guzman-Ayala
A1 Andrew JK Williamson
A1 Miroslav Hejna
A1 Anthony D Whetton
A1 Jun S. Song
A1 Miguel Ramalho-Santos
YR 2019
UL http://biorxiv.org/content/early/2019/06/04/659995.abstract
AB Stem and progenitor cells undergo a global elevation of nascent transcription, or hypertranscription, during key developmental transitions involving rapid cell proliferation. The chromatin remodeler Chd1 binds to genes transcribed by RNA Polymerase (Pol) I and II and is required for hypertranscription in embryonic stem (ES) cells in vitro and the early post-implantation epiblast in vivo. Biochemically, Chd1 has been shown to facilitate transcription at least in part by removing nucleosomal barriers to elongation, but its mechanism of action in stem cells remains poorly understood. Here we report a novel role for Chd1 in the repair of promoter-proximal endogenous double-stranded DNA breaks (DSBs) in ES cells. An unbiased proteomics approach revealed that Chd1 interacts with several DNA repair factors including Atm, Parp1, Kap1 and Topoisomerase 2β. We show that wild-type ES cells display high levels of phosphorylated H2A.X and Kap1 at chromatin, notably at rDNA in the nucleolus, in a Chd1-dependent manner. Loss of Chd1 leads to an extensive accumulation of DSBs at Chd1-bound Pol II-transcribed genes and rDNA. Genes prone to DNA breaks in Chd1 KO ES cells tend to be 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 endogenous DNA breaks, with important implications for developmental and cancer biology.