RT Journal Article
SR Electronic
T1 Elevated glucose increases genomic instability by inhibiting nucleotide excision repair
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202101159
DO 10.26508/lsa.202101159
VO 4
IS 10
A1 Alexandra K Ciminera
A1 Sarah C Shuck
A1 John Termini
YR 2021
UL https://www.life-science-alliance.org/content/4/10/e202101159.abstract
AB We investigated potential mechanisms by which elevated glucose may promote genomic instability. Gene expression studies, protein measurements, mass spectroscopic analyses, and functional assays revealed that elevated glucose inhibited the nucleotide excision repair (NER) pathway, promoted DNA strand breaks, and increased levels of the DNA glycation adduct N2-(1-carboxyethyl)-2ʹ-deoxyguanosine (CEdG). Glycation stress in NER-competent cells yielded single-strand breaks accompanied by ATR activation, γH2AX induction, and enhanced non-homologous end-joining and homology-directed repair. In NER-deficient cells, glycation stress activated ATM/ATR/H2AX, consistent with double-strand break formation. Elevated glucose inhibited DNA repair by attenuating hypoxia-inducible factor-1α–mediated transcription of NER genes via enhanced 2-ketoglutarate–dependent prolyl hydroxylase (PHD) activity. PHD inhibition enhanced transcription of NER genes and facilitated CEdG repair. These results are consistent with a role for hyperglycemia in promoting genomic instability as a potential mechanism for increasing cancer risk in metabolic disease. Because of the pleiotropic functions of many NER genes beyond DNA repair, these results may have broader implications for cellular pathophysiology.