HMGB1 and HMGB2 Are O4-Alkylthymidine-Binding Proteins

Exposure to endogenous and exogenous sources of alkylating agents leads to DNA lesions that can impair cell survival and confer genome instability by eliciting mutations during DNA replication and transcription. Among the DNA alkylation adducts, O4-alkylthymidine (O4-alkyldT) lesions are poorly repaired in mammalian cells, and not much is known about the cellular proteins involved in the recognition of these lesions. Here, we found that HMGB1 and HMGB2 bind directly and preferentially to O4-alkyldT-containing DNA. CRISPR-Cas9-mediated ablation of HMGB1 or HMGB2 led to an attenuated level of transcriptional bypass of these lesions, indicating diminished repair of O4-alkyldT lesions. Together, we identify HMGB1 and HMGB2 as O4-alkyldT recognition proteins, and our work suggests the functions of these proteins in promoting the repair of O4-alkyldT lesions.