Abstract
Activation of the p53 tumor suppressor upon DNA damage elicits either cell cycle arrest or apoptosis, and the precise mechanism governing cell fate after p53 response has not been well defined. Through genomic analysis, we have identified the ribosomal protein S27-like (RPS27L) as a novel p53 transcriptional target gene. Although RPS27L mRNA levels were consistently induced after diverse p53 activating signals, its change in protein level was stimuli-dependent: it was up-regulated when cells were arrested in response to DNA-damaging agents Adriamycin or VP16 but was down-regulated when cells underwent apoptosis in response to antimetabolite agent 5-fluorouracil. RPS27L is a nuclear protein that forms nuclear foci upon DNA damage. Depletion of RPS27L resulted in deficiency in DNA damage checkpoints, leading to conversion of DNA damage-induced p53 response from cell cycle arrest to apoptosis. We further show that RPS27L positively regulates p21 protein expression. Through this mechanism, RPS27L induction by p53 facilitates p21-mediated cell cycle arrest and protects against DNA damage-induced apoptosis. Thus, RPS27L modulates DNA damage response and functions as a part of the control switch to determine cell fate to DNA damage-p53 response.
Highlights
In response to DNA damage, mammalian cells activate a protection system to enable repair to continue normal life cycle or they may activate the apoptotic machinery in the face of excessive and irreparable damage [1]
We further found that the reduced p21 protein level was not due to inhibited p21 transcription because p21 mRNA levels were not www.aacrjournals.org significantly changed in ribosomal protein S27-like (RPS27L)-depleted cells compared with the control cells (Fig. 5B)
We identify the RPS27L protein as a novel p53 transcriptional target participating in DNA damage response
Summary
In response to DNA damage, mammalian cells activate a protection system to enable repair to continue normal life cycle or they may activate the apoptotic machinery in the face of excessive and irreparable damage [1]. The tumor suppressor p53 is believed to play important roles in DNA damage response. Major consequences of p53 activation after DNA damage include the induction of cell cycle arrest, senescence, or apoptosis [6,7,8]. It is well known that p53-dependent cell cycle arrest is primarily mediated through transcriptional induction of the cyclin-dependent kinase inhibitor p21 [9, 10]. The mechanism for p53-induced apoptosis, is less clear. The mechanism for p53-induced apoptosis, is less clear. p53 might induce apoptosis
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