DNA repair enzyme flaw raises Alzheimer’s risk signal

GHKL ATPases are a class of enzymes that use ATP energy to drive biological processes, including DNA repair. Two proteins in this class, PMS2 and MLH1, are part of the DNA mismatch repair (MMR) system: a cellular mechanism that recognizes and corrects errors in DNA before they cause harm. Variants in these proteins were already linked to cancer risk, but their precise functional effects were unclear.

Two amino acids cooperate in a key catalytic step

Researchers published a study in eLife examining how GHKL ATPases break down ATP to perform their function. They found that two amino acids cooperate during an early step in that process. One amino acid (glutamate) positions a water molecule; the second amino acid then acts together with the first to accept a proton and drive the reaction forward. Mutating only one of the two partially stalls the process. Mutating both stops it entirely.

The researchers then applied this framework to clinically reported variants in human PMS2 and MLH1. Variants actually found in patients substantially reduced ATP-processing activity, indicating genuine functional impairment in those individuals.

From cancer gene to aging relevance

MMR defects are primarily associated with Lynch syndrome and colorectal cancer. But impaired DNA repair in neurons is also linked to neurodegenerative diseases, including Alzheimer’s. The new mechanistic insights provide a more precise way to evaluate variants of uncertain significance: not just whether a variant exists, but whether it actually damages enzyme function. That is relevant for cancer risk assessment and, potentially, neurodegeneration research. The link to Alzheimer’s is indirect at this stage and requires further investigation.

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