Abstract
Postmitotic neurons depend on continuous DNA repair to preserve genome integrity, yet the polymerases supporting repair-associated DNA synthesis remain poorly defined. Here, we identify DNA polymerase kappa (POLK), a Y-family translesion synthesis polymerase studied predominantly in proliferating cells, as a regulator of DNA synthesis and genome maintenance in postmitotic neurons. Using primary mouse cortical neurons and human induced pluripotent stem cell-derived forebrain neurons, we show that POLK localizes near newly synthesized DNA and repair-associated proteins, including ubiquitinated PCNA. POLK depletion reduces DNA synthesis in both mouse and human neurons and promotes nuclear and organelle remodeling, p21-associated senescence-like stress, inflammatory responses, and increased p38 MAPK immunoreactivity. In an Alzheimer's disease-risk genetic background, POLK depletion also increases cytoplasmic double-stranded DNA and tau phosphorylation. Conversely, POLK overexpression enhances neuronal DNA synthesis while reducing DNA damage-associated signals, p38 MAPK immunoreactivity, cytoplasmic DNA, and Alzheimer's disease-relevant phenotypes. These findings uncover a role for POLK in postmitotic neuronal genome maintenance, linking specialized DNA polymerase function to neuronal stress and vulnerability relevant to aging and neurodegeneration.
Full Text Availability
The license terms selected by the author(s) for this preprint version do not permit archiving in PMC. The full text is available from the preprint server.
