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Abstract
DNA mismatch repair (MMR) preserves genome integrity by correcting replication errors and triggering apoptosis in response to certain DNA lesions. Central to this pathway is the MutLα complex, composed of MLH1 and PMS2, whose ATPase activities are essential for repair. This study examines ATPase‑domain mutations in MLH1 and PMS2 in mammalian cells and shows that MLH1 ATPase defects impair mismatch repair and 6‑thioguanine cytotoxicity more strongly than equivalent PMS2 mutations, revealing functional asymmetry within MutLα. A second line of investigation shows that reduced expression of the nucleotide‑pool regulator DCTD increases resistance to 6‑thioguanine in human cells, whereas Dctd‑null mouse cells do not display this phenotype, suggesting adaptive maintenance of nucleotide balance. Together, these findings clarify distinct roles for MutLα subunits in repair and identify DCTD as a contributor to MMR‑dependent DNA damage responses.