NTHL1 is a bifunctional DNA N-glycosylase with AP-lyase activity that initiates base excision repair (BER), the primary pathway for repairing oxidative DNA damage 1. The enzyme releases damaged DNA bases by cleaving N-glycosidic bonds and subsequently cleaves phosphodiester bonds 3' to apurinic/apyrimidinic sites through beta-elimination 1. NTHL1 primarily recognizes oxidative pyrimidine lesions and 8-oxoguanine damage, and can function within nucleosomes without disrupting chr16 structure 1. Germline biallelic NTHL1 mutations cause NTHL1-associated polyposis (NAP), an autosomal recessive adenomatous polyposis syndrome with significantly increased colorectal and extracolonic cancer risk 2. Individuals with biallelic mutations demonstrate a broader tumor spectrum than those with MUTYH mutations, including breast and unusual cancers 3. Loss-of-function NTHL1 variants show enriched association with colorectal cancer risk 4. Additionally, NTHL1 expression levels modulate chemotherapy sensitivity; elevated NTHL1 expression enhances cisplatin sensitivity in non-small cell lung cancer cells, possibly through altered interactions with nucleotide excision repair proteins 5. These findings establish NTHL1 as a critical genomic caretaker whose dysfunction contributes to cancer predisposition and chemotherapy resistance 6.