DOC45, a Novel DNA Damage–Regulated Nucleocytoplasmic ATPase That Is Overexpressed in Multiple Human Malignancies

Abstract

In this article, we report the characterization of a novel DNA damage-regulated gene, named DNA damageregulated overexpressed in cancer 45 (DOC45). Our results indicate that DNA damage-inducing agents, including doxorubicin (adriamycin), etoposide, and ionizing and UV radiation, strongly downregulate DOC45 expression, whereas endoplasmic reticulum stress-inducing agents do not. Our results also indicate that DOC45 is overexpressed in several human malignancies, including cancers of the colon, rectum, ovary, lung, stomach, and uterus. DOC45 harbors conserved nucleotide triphosphate-binding motifs and is capable of ATP hydrolysis, findings that highlight its function as a novel ATPase. Although predominantly cytoplasmic, DOC45 exhibits a characteristic nucleocytoplasmic distribution and, on inhibition of nuclear export, predominantly accumulates in the nucleoli. These results suggest that DOC45 may shuttle between nucleus and cytoplasm to carry out its function. Our results also indicate that DOC45 expression is enhanced during oncogenic Ras-mediated transformation and that its expression is linked to phosphoinositide 3-kinase signaling pathway. Furthermore, short hairpin RNA-mediated knockdown of DOC45 in human colon cancer cells inhibits their proliferation and enhances cellular sensitivity to doxorubicin-induced cell death, suggesting that DOC45 plays an important role in cell proliferation and survival. Collectively, our results indicate that DOC45 is a novel ATPase that is linked to cellular stress response and tumorigenesis, and may also serve as a valuable tumor marker. Mol Cancer Res; 8(1); 57-66. ©2010 AACR.

A Universally Conserved ATPase Regulates the Oxidative Stress Response in Escherichia coli

“…The possible involvement of hOla1 in regulating the stress response is consistent with data showing its down-regulation in cells treated with DNA-damaging agents or UV light (9). hOla1 overexpression has been observed in many tumor cells (9 -11), which could indicate that at high hOla1 concentrations the cellular response to potentially mutagenic substances is impaired.…”

OLA1, a Translational Regulator of p21, Maintains Optimal Cell Proliferation Necessary for Developmental Progression

“…Whereas most null mutations of the YchF homologue in yeasts are nonlethal (7), inactivation of TcYchF by RNA interference (RNAi) in trypanosomes (Trypanosoma cruzi) inhibited the protozoan's growth (4). We (6) and others (8) reported that OLA1 knockdown (KD) in human cells under normal culture conditions had, depending on the origin of the cell lines used, either a negative effect or no effect on cell proliferation. However, under multiple cellular stresses, including oxidative stress, OLA1 KD promoted cell survival (9) by "gating" ISR and the expression of downstream proapoptotic factors, such as CHOP (6).…”

Redox Activation of the Universally Conserved ATPase YchF by Thioredoxin 1

“…Disclosing cellular targets of YchF/Ola1 is of significant importance because human Ola1 appears to play a major role in pathogenicity and disease development. Ola1 expression is regulated by DNA damage (32,46) and is upregulated in many human tumors (46). On the other hand, a downregulation of Ola1 is observed in interferon b-treated multiple sclerosis patients (14).…”

“…In eukaryotic cells, the thioredoxin-interacting protein, Txnip, has been shown to be a key element of cellular redox regulation because it inhibits thioredoxin activity (34). Txnip promotes apoptosis, increases ROS production, and influences metastasis (55), phenotypes which have also been associated with increased Ola1 concentrations (23,46,56).…”

“…1A). A possible role in DNA repair was also postulated because human hOla1 is downregulated upon DNA damage and upregulated in many tumors (46). This was validated by the observation that hOla1 interacts with BRCA1 (breast cancer-associated gene 1) at the centrosome and that depletion of hOla1 induced centrosome fragmentation (29).…”