Oxidative stress is implicated in carcinogenesis, aging, and neurodegenerative diseases. The E3 ligase C terminus of Hsc-70 interacting protein (CHIP) has a protective role against various stresses by targeting damaged proteins for proteasomal degradation, and thus maintains protein quality control. However, the detailed mechanism by which CHIP protects cells from oxidative stress has not been demonstrated. Here, we show that depletion of CHIP led to elevated Endonuclease G (EndoG) levels and enhanced cell death upon oxidative stress. In contrast, CHIP overexpression reduced EndoG levels, and resulted in reduced or no oxidative stress-induced cell death in cancer cells and primary rat cortical neurons. Under normal conditions Hsp70 mediated the interaction between EndoG and CHIP, downregulating EndoG levels in a Hsp70/proteasome-dependent manner. However, under oxidative stress Hsp70 no longer interacted with EndoG, and the stabilized EndoG translocated to the nucleus and degraded chromosomal DNA. Our data suggest that regulation of the level of EndoG by CHIP in normal conditions may determine the sensitivity to cell death upon oxidative stress. Indeed, injection of H2O2 into the rat brain markedly increased cell death in aged mice compared with young mice, which correlated with elevated levels of EndoG and concurrent downregulation of CHIP in aged mice. Taken together, our findings demonstrate a novel protective mechanism of CHIP against oxidative stress through regulation of EndoG, and provide an opportunity to modulate oxidative stress-induced cell death in cancer and aging.

Affecting approximately one in nine women during their life time, breast cancer is one of the most common causes of cancer and cancer-related mortality in women (Alberg and Helzlsouer 1997;Paterson 1998). Although most breast cancers are sporadic, 5-10% of breast cancers are heritable. Germ-line mutations in the BRCA1 gene are found in almost all of the families with inherited breast and ovarian cancers and about half of the families with only breast cancer (Easton et al. 1993; for review, see Feunteun and Lenoir 1996). Because loss of heterozygosity is detected in the BRCA1 gene in cancer cells from BRCA1 mutation carriers, BRCA1 is considered to be a tumor suppressor (Smith et al. 1992). Although evidence indicates that BRCA1 is involved in maintaining genome integrity, the biochemical functions of BRCA1 and how the BRCA1 mutations contribute to cancer development are poorly understood. In this paper, we focus on how the presence of DNA damage is transmitted to BRCA1 and speculate on how BRCA1 functions as a tumor suppressor. For a more general overview of BRCA1 function(s) and its role as a tumor suppressor, see one of the excellent reviews published recently (Chen et al.