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.