Abstract
The cellular DNA damage response (DDR) ensures genomic stability and protects against genotoxic stresses. Conversely, defects in the DDR contribute to genome instability, with the resulting accumulated genetic changes capable of inducing neoplastic transformation. Thus, DDR is central to both the mechanism of oncogenesis and cancer therapy. Specifically, DDR is accomplished via a complicated meshwork of evolutionary conserved proteins, including ATM, ATR, and phospho-H2AX (γH2AX). GLTSCR2 is a nucleolar protein believed to function as a tumor suppressor, although its exact molecular mechanisms have yet to be fully elucidated. As a result of our research pertaining to the role of GLTSCR2 in tumor suppression, we have determined that GLTSCR2 is involved in DDR. Under genotoxic conditions, such as cellular exposure to UV radiation or radiomimetic drugs, GLTSCR2 expression increased and later mobilized to the nucleoplasm. Moreover, GLTSCR2 knockdown attenuated both the presence of phospho-H2AX at the nuclear foci and the phosphorylation of multiple DDR proteins, including ATM, ATR, Chk2, Chk1, and H2AX. In addition, the decreased expression of GLTSCR2 sensitized cells to DNA damage, delayed DNA repair, and abolished G2/M checkpoint activation. Our observations indicate that GLTSCR2 is a key component of DDR and GLTSCR2 seems to act as a tumor suppressor by participating in optimal DDR because DNA damage is a frequent and crucial event in oncogenesis.