Double-stranded breaks (DSBs) are cytotoxic DNA lesions caused by oxygen 
radicals, ionizing radiation, and radiomimetic chemicals. Increasing 
understanding of DNA damage signaling has provided an ever-expanding list of 
modulators reported to orchestrate DNA damage repair and ataxia telangiectasia 
mutated (ATM) is the master regulator and main transducer of the DSB response. 
Increasingly, it is being realized that DNA damage response is a synchronized 
and branched network that functionalizes different molecular cascades to 
activate special checkpoints, thus temporarily arresting progression of the cell 
cycle while damage is being assessed and processed. It is noteworthy that both 
nutrigenetics and nutrigenomics have revolutionized the field of molecular 
biology and rapidly accumulating experimental evidence has started to shed light 
on biological activities of a wide range of phytochemicals reported to modulate 
cell cycle, DNA repair, cell growth, differentiation and apoptosis as evidenced 
by cell-based studies. In this review, we have attempted to provide an overview 
of DNA damage signaling, how ATM signaling regulates tumor necrosis 
factors-related apoptosis inducing ligand (TRAIL)-induced intracellular network. 
We also illuminate on how resveratrol, epigallocatechin gallate, curcumin, 
jaceosidin, cucurbitacin, apigenin, genistein, and others trigger activation of 
ATM in different cancer cells as well as agents for ATM inactivation. 
Understanding the interplay of TRAIL-induced intracellular signaling and ATM 
modulation of downstream effectors is very important. This holds particularly 
for a reconceptualization of the apparently paradoxical roles and 
therapeutically targetable for enhancing the response to DNA damage-inducing 
therapy.