{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nDNA repair glycosylases that remove oxidized pyrimidine lesions play critical roles in maintaining genomic integrity by excising toxic bases such as thymine glycol from DNA. In mammals, several enzymes, including the homologues of bacterial Endonuclease III (mNTH1) and Endonuclease VIII (NEIL1), exhibit overlapping substrate specificity. For example, NEIL1 has been shown to efficiently remove thymine glycol and 5‐hydroxyuracil — in both double‐ and single‐stranded DNA — and even acts on mispaired bases in U:C and T:C mismatches, suggesting a back‐up function to mNTH1 (PMIDs."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " Moreover, alternative glycosylase activities evident in mNth1 knockout mice indicate that complementary repair pathways exist to resolve oxidative DNA damage when the primary enzyme is absent."}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nThe activities of these glycosylases extend across both nuclear and mitochondrial compartments. In mitochondria, mNTH1 appears to be the principal enzyme for thymine glycol repair, while other glycosylases contribute to the removal of additional oxidized pyrimidines such as 5,6-dihydrouracil and 5-hydroxycytosine (PMIDs."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " In addition, impaired glycosylase activities have been linked to defects at telomeric repeats, where oxidative damage potentiates telomere attrition, fragility, and recombination, thereby emphasizing the synergistic role of base excision repair and telomerase in telomere maintenance (PMID."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond lesion removal, the coordinated actions of these enzymes are essential for preventing mutagenesis and preserving genomic stability. Repair of oxidatively induced base lesions such as FapyG and FapyA is largely mediated by OGG1 and NTH1 in different cellular contexts, while NEIL1 also contributes in mitochondria when conventional glycosylases are compromised. The loss or mutation of these enzymes leads to increased oxidative base damage, the accumulation of replication stress and double-stranded DNA breaks, and even tumor predisposition, as seen in double knockout models and in knockin mice carrying a dominant NTHL1 (NTH1) variant (PMIDs."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "11"}]}, {"type": "t", "text": " Furthermore, while the interplay between the base excision repair and mismatch repair systems modulates cellular sensitivity to oxidative stress, it is clear that multiple, sometimes overlapping, pathways are integral to mitigating the potentially deleterious mutagenic consequences of reactive oxygen species."}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Masashi Takao, Shin-ichiro Kanno, Tatsuya Shiromoto, et al. 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