The p53 network: cellular and systemic DNA damage responses in cancer and aging

The tumor protein TP53 is the single most frequently mutated gene in human cancer. p53 is a central regulator of the DNA damage response that impacts cancer and aging. p53 is regulated by non-cell-autonomous mechanisms and exerts systemic consequences. Therapeutic strategies targeting p53 in cancer have recently made significant progress. The tumor protein TP53 gene, encoding the cellular tumor antigen p53, is the single most frequently mutated gene in human cancers. p53 plays a central role in responding to DNA damage and determines the outcome of the DNA damage checkpoint response by regulating cell cycle arrest and apoptosis. As a consequence of this function, dysfunctional p53 results in cells that, despite a damaged genome, continue to proliferate thus fueling malignant transformation. New insights have recently been gained into the complexity of the p53 regulation of the DNA damage response (DDR) and how it impacts a wide variety of cellular processes. In addition to cell-autonomous signaling mechanisms, non-cell-autonomous regulatory inputs influence p53 activity, which in turn can have systemic consequences on the organism. New inroads have also been made toward therapeutic targeting of p53 that for a long time has been anticipated. The tumor protein TP53 gene, encoding the cellular tumor antigen p53, is the single most frequently mutated gene in human cancers. p53 plays a central role in responding to DNA damage and determines the outcome of the DNA damage checkpoint response by regulating cell cycle arrest and apoptosis. As a consequence of this function, dysfunctional p53 results in cells that, despite a damaged genome, continue to proliferate thus fueling malignant transformation. New insights have recently been gained into the complexity of the p53 regulation of the DNA damage response (DDR) and how it impacts a wide variety of cellular processes. In addition to cell-autonomous signaling mechanisms, non-cell-autonomous regulatory inputs influence p53 activity, which in turn can have systemic consequences on the organism. New inroads have also been made toward therapeutic targeting of p53 that for a long time has been anticipated. a population of heterogenous stromal cells present in the tumor microenvironment that are involved in crosstalk with cancer cells and leukocytes and regulate immune evasion of tumors. Mutants containing genetic alterations that change the folding of the encoded protein compared with the wild type, resulting in change of protein functions regulated by secondary structure. mutants containing genetic alterations that disrupt protein–DNA interactions, resulting in alteration of protein function regulated by DNA binding. DNA damage response is a network of cellular pathways that sense, signal, and induce a response (such as repair or cell death) to DNA lesions to preserve genome integrity. a rare, inherited familial predisposition to a wide range of cancers due to germline mutations in the TP53 gene. mutants containing a genetic alteration where a single base pair in a codon is substituted to alter the genetic code such that the resulting amino acid is different from the usual amino acid at that position. Missense mutations can alter the protein function. a disorder that results in physiological aging in an accelerated timespan in a tissue-specific manner, causing the individuals to exhibit aging-associated features in affected tissues. the property of senescent cells to express and secrete a variety of extracellular factors such as cytokines, chemokines, and proteases to stimulate the immune clearance of potentially tumorigenic cells, and promote tissue regeneration and wound healing.