PPP4R3A (protein phosphatase 4 regulatory subunit 3A), also known as SMEK1, is a regulatory subunit of serine/threonine-protein phosphatase 4 that functions in multiple cellular processes. As part of the PPP4C-PPP4R2-PPP4R3A complex, it dephosphorylates gamma-H2AX (H2AX phosphorylated at Ser-140), playing a critical role in DNA double-strand break repair 1. Beyond DNA damage response, PPP4R3A regulates microtubule stability through interaction with kinesin family member 2A (Kif2a), facilitating axonal outgrowth and mitochondrial trafficking 2. The gene also functions as a nuclear chaperone for cleaved Wnt receptor Ryk, regulating cortical neurogenesis and neural cell fate determination 3. In metabolic regulation, SMEK1 controls glucose uptake and adipogenesis through AMPK signaling 4. Clinically, a protective variant (rs2273647-T) in PPP4R3A is associated with reduced Alzheimer's disease risk and slowed cognitive decline 1. PPP4R3A exhibits tumor suppressor properties in leukemia, where overexpression increases apoptosis and reduces cell survival 5. The protein's dysregulation occurs across multiple cancer types and neurodegenerative diseases, making it a potential therapeutic target.