Clusterin [CLU, a.k.a. TRPM-2, SGP-2, or ionizing radiation (IR)-induced protein-8 (XIP8)] was implicated in apoptosis, tissue injury, and aging. Its function remains elusive. We reisolated CLU͞XIP8 by yeast twohybrid analyses using as bait the DNA double-strand break repair protein Ku70. We show that a delayed (2-3 days), low-dose (0.02-10 Gy) IR-inducible nuclear CLU͞XIP8 protein coimmunoprecipitated and colocalized (by confocal microscopy) in vivo with Ku70͞Ku80, a DNA damage sensor and key double-strand break repair protein, in human MCF-7:WS8 breast cancer cells. Overexpression of nuclear CLU͞XIP8 or its minimal Ku70 binding domain (120 aa of CLU͞XIP8 C terminus) in nonirradiated MCF-7:WS8 cells dramatically reduced cell growth and colony-forming ability concomitant with increased G 1 cell cycle checkpoint arrest and increased cell death. Enhanced expression and accumulation of nuclear CLU͞XIP8-Ku70͞Ku80 complexes appears to be an important cell death signal after IR exposure.