DNA polymerase kappa supports repair-associated DNA synthesis and genome maintenance in postmitotic neurons

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.