期刊
EMBO JOURNAL
卷 38, 期 1, 页码 -出版社
WILEY
DOI: 10.15252/embj.201899242
关键词
base excision repair; DNA demethylation; stem cell differentiation; small ubiquitin-like modifier
资金
- Swiss National Science Foundation [SNSF_138153, 156467]
- Walter Honegger Foundation, Zurich
During active DNA demethylation, 5-methylcytosine (5mC) is oxidized by TET proteins to 5-formyl-/5-carboxylcytosine (5fC/5caC) for replacement by unmethylated C by TDG-initiated DNA base excision repair (BER). Base excision generates fragile abasic sites (AP-sites) in DNA and has to be coordinated with subsequent repair steps to limit accumulation of genome destabilizing secondary DNA lesions. Here, we show that 5fC/5caC is generated at a high rate in genomes of differentiating mouse embryonic stem cells and that SUMOylation and the BER protein XRCC1 play critical roles in orchestrating TDG-initiated BER of these lesions. SUMOylation of XRCC1 facilitates physical interaction with TDG and promotes the assembly of a TDG-BER core complex. Within this TDG-BERosome, SUMO is transferred from XRCC1 and coupled to the SUMO acceptor lysine in TDG, promoting its dissociation while assuring the engagement of the BER machinery to complete demethylation. Although well-studied, the biological importance of TDG SUMOylation has remained obscure. Here, we demonstrate that SUMOylation of TDG suppresses DNA strand-break accumulation and toxicity to PARP inhibition in differentiating mESCs and is essential for neural lineage commitment.
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