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XB-ART-56334
Elife January 1, 2019; 8

NEIL1 and NEIL2 DNA glycosylases protect neural crest development against mitochondrial oxidative stress.

Han D , Schomacher L , Schüle KM , Mallick M , Musheev MU , Karaulanov E , Krebs L , von Seggern A , Niehrs C .


Abstract
Base excision repair (BER) functions not only in the maintenance of genomic integrity but also in active DNA demethylation and epigenetic gene regulation. This dual role raises the question if phenotypic abnormalities resulting from deficiency of BER factors are due to DNA damage or impaired DNA demethylation. Here we investigate the bifunctional DNA glycosylases/lyases NEIL1 and NEIL2, which act in repair of oxidative lesions and in epigenetic demethylation. Neil-deficiency in Xenopus embryos and differentiating mouse embryonic stem cells (mESCs) leads to a surprisingly restricted defect in cranial neural crest cell (cNCC) development. Neil-deficiency elicits an oxidative stress-induced TP53-dependent DNA damage response, which impairs early cNCC specification. Epistasis experiments with Tdg-deficient mESCs show no involvement of epigenetic DNA demethylation. Instead, Neil-deficiency results in oxidative damage specific to mitochondrial DNA, which triggers a TP53-mediated intrinsic apoptosis. Thus, NEIL1 and NEIL2 DNA glycosylases protect mitochondrial DNA against oxidative damage during neural crest differentiation.

PubMed ID: 31566562
PMC ID: PMC6768664
Article link: Elife
Grant support: [+]

Species referenced: Xenopus
Genes referenced: apex1 bak1 bcl2 bcl2l1 ccng1 chek1 neil1 neil2 neil3 pam pax3 pax6 snai2 sox1 sox10 tbp tdg tp53
GO keywords: neural crest cell development


Article Images: [+] show captions
References [+] :
Abbotts, Human AP endonuclease 1 (APE1): from mechanistic insights to druggable target in cancer. 2010, Pubmed