p18 was first identified as a factor associated with a macromolecular tRNA synthetase complex. Here we describe the mouse p18 loss-of-function phenotype and a role for p18 in the DNA damage response. Inactivation of both p18 alleles caused embryonic lethality, while heterozygous mice showed high susceptibility to spontaneous tumors. p18 was induced and translocated to the nucleus in response to DNA damage. Expression of p18 resulted in elevated p53 levels, while p18 depletion blocked p53 induction. p18 directly interacted with ATM/ATR in response to DNA damage. The activity of ATM was dependent on the level of p18, suggesting the requirement of p18 for the activation of ATM. Low p18 expression was frequently observed in different human cancer cell lines and tissues. These results suggest that p18 is a haploinsufficient tumor suppressor and a key factor for ATM/ATR-mediated p53 activation.
Bibliographical noteFunding Information:
We thank Tae Hee Han for providing the RNAs isolated from leukemia patients; Dae Sik Lim, Michael B. Kastan, Stephen J. Elledge, Yosef Shiloh, and Han Woong Lee for materials; and Kenji Kamino for consultations regarding the tumor analyses in mice. This work was supported by a grant from National Creative Research Initiatives of the Ministry of Science and Technology, Korea.
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)