p53 and RAD9, the DNA Damage Response, and Regulation of Transcription Networks

Abstract

The way cells respond to DNA damage is important since inefficient repair or misrepair of lesions can have deleterious consequences, including mutation, genomic instability, neurodegenerative disorders, premature aging, cancer or death. Whether damage occurs spontaneously as a byproduct of normal metabolic processes, or after exposure to exogenous agents, cells muster a coordinated, complex DNA damage response (DDR) to mitigate potential harmful effects. A variety of activities are involved to promote cell survival, and include DNA repair, DNA damage tolerance, as well as transient cell cycle arrest to provide time for repair before entry into critical cell cycle phases, an event that could be lethal if traversal occurs while damage is present. When such damage is prolonged or not repairable, senescence, apoptosis or autophagy is induced. One major level of DDR regulation occurs via the orchestrated transcriptional control of select sets of genes encoding proteins that mediate the response. p53 is a transcription factor that transactivates specific DDR downstream genes through binding DNA consensus sequences usually in or near target gene promoter regions. The profile of p53-regulated genes activated at any given time varies, and is dependent upon type of DNA damage or stress experienced, exact composition of the consensus DNA binding sequence, presence of other DNA binding proteins, as well as cell context. RAD9 is another protein critical for the response of cells to DNA damage, and can also selectively regulate gene transcription. The limited studies addressing the role of RAD9 in transcription regulation indicate that the protein transactivates at least one of its target genes, p21/waf1/cip1, by binding to DNA sequences demonstrated to be a p53 response element. NEIL1 is also regulated by RAD9 through a similar DNA sequence, though not yet directly verified as a bonafide p53 response element. These findings suggest a novel pathway whereby p53 and RAD9 control the DDR through a shared mechanism involving an overlapping network of downstream target genes. Details and unresolved questions about how these proteins coordinate or compete to execute the DDR through transcriptional reprogramming, as well as biological implications, are discussed.

Wnt pathway is involved in 5-FU drug resistance of colorectal cancer cells

“…p53 plays a major role in cellular responses to genomic aberrations, such as DNA damage 24 . Activation and stabilization of p53 lead to cell cycle arrest, DNA repair, or apoptosis 25 .…”

Resveratrol induced premature senescence and inhibited epithelial-mesenchymal transition of cancer cells via induction of tumor suppressor Rad9

“…In addition, ectopic Rad9 expression in MDA-MB 231 cells and H1299 cells resulted in induced senescence by the upregulation of p21 and the simultaneous attenuation of cellular migration and invasion abilities with concomitant downregulation of Slug and thereby, suppressed the tumorigenicity in vitro and in a xenograft mouse model [11]. Although Rad9 is a potential tumor suppressor in breast and lung cancers, and can selectively regulate genes that contribute to DDR or EMT, such as p21 [12], NEIL1 [13], and Slug [11], other Rad9-targeting genes and factors that may down- or up-regulate the transcription of Rad9 are not yet to be identified [14].…”

Sublethal Doses of Inorganic Mercury Induce Dose-Depended Upregulation of RPA1 Content and Inhibit p53 Expression in the Brain of Rainbow Trout (Oncorhynchus mykiss)

“…One of first discovered function of p53 protein was confirmed as a stress sensor. Protein p53 is involved in the regulation of many vital processes, including cell cycle, the initiation of apoptosis, transcriptional activity and DNA repair (Lieberman et al, 2017). Later, number evidences were lighted that p53 regulates gene expression to maintain efficacy of cell adaptation to environmental context.…”