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Abstract
Occurrence of DNA damage in a cell activates the DNA damage response, a survival mechanism that ensures genomics stability. Two key members of the DNA damage response are the tumor suppressor p53, which is the most frequently mutated gene in cancers, and MDC1, which is a central adaptor that recruits many proteins to sites of DNA damage. Here we characterize the in vitro interaction between p53 and MDC1 and demonstrate that p53 and MDC1 directly interact. The p53-MDC1 interaction is mediated by the tandem BRCT domain of MDC1 and the C-terminal domain of p53. We further show that both acetylation of lysine 382 and phosphorylation of serine 392 in p53 enhance the interaction between p53 and MDC1. Additionally, we demonstrate that the p53-MDC1 interaction is augmented upon the induction of DNA damage in human cells. Our data suggests a new role for acetylation of lysine 382 and phosphorylation of serine 392 in p53 in the cellular stress response and offers the first evidence for an interaction involving MDC1 that is modulated by acetylation.
Highlights
Genomic instability is a hallmark of cancer cells [1]
Our results suggest a new role for acetylated K382 (Ac-K382) and phosphorylated serine 392 (S392) of p53 in the cellular stress response and provide, if they occur in vivo, the first evidence for an interaction involving MDC1 that is modulated by acetylation
MDC1 was retrieved by the anti-HA antibodies only following NCS treatment as detected when blotting with a specific antibodies directed against MDC1 (Figure 1c)
Summary
Genomic instability is a hallmark of cancer cells [1]. The primary cause of genomic instability is DNA damage [2]. Proper activation of the DDR utilizes a complex, rapid and tightly regulated cascade of proteinprotein interactions leading to cell-cycle arrest, DNA repair, apoptosis or cellular senescence [3,4,5,6,7]. The cellular response to DNA damage is driven by numerous post-translational modifications (PTMs) of histones and other proteins, which include phosphorylation, poly(ADPribosyl)ation, acetylation, ubiquitylation and sumoylation [7]. When the histones are post-transcriptionally modified, they can directly regulate the DDR by changing the chromatin structure at sites of DNA damage [8,9]. Protein-protein interactions, which are required for proper DNA repair, checkpoint activation and apoptosis are tightly regulated by PTMs [7]
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