Which of the following is known as the guardian of the genome
Correct Answer: P53
Description: Ref Robbins 7/e p302; 303; 304;9/e p293 TP53 Gene: Guardian of the Genome The p53-encoding tumor suppressor gene, TP53, is one of the most commonly mutated genes in human cancers. The p53 protein thwas neoplastic transformation by three interlocking mechanisms: activation of temporary cell cycle arrest (termed quiescence), induction of permanent cell cycle arrest (termed senescence), or triggering of pro- grammed cell death (termed apoptosis). If Rb "senses" external signals, p53 can be viewed as a central monitor of internal stress, directing the stressed cells toward one of these three pathways. A variety of stresses trigger the p53 response pathways, including anoxia, inappropriate oncoprotein activity (e.g., MYC or RAS), and damage to the integrity of DNA. By managing the DNA damage response, p53 plays a central role in maintaining the integrity of the genome, as described next. In nonstressed, healthy cells, p53 has a sho half-life (20 minutes) because of its association with MDM2, a protein that targets p53 for destruction. When the cell is stressed, for example, by an assault on its DNA, "sensors" that include protein kinases such as ATM (ataxia telangiectasia mutated) are activated. These activated complexes catalyze post-translational modifications in p53 that release it from MDM2 and increase its half-life and enhance its ability to drive the transcription of target genes. Hundreds of genes whose transcription is triggered by p53 have been found. These genes suppress neoplastic transformation by three mechanisms: * p53-mediated cell cycle arrest may be considered the primor- dial response to DNA damage (Fig. 5-23). It occurs late in the G1 phase and is caused mainly by p53-dependent transcription of the CDKI gene CDKN1A (p21). The p21 protein, as described earlier, inhibits cyclin-CDK com- plexes and prevents phosphorylation of Rb, thereby arresting cells in the G1 phase. Such a pause in cell cycling is welcome, because it gives the cells "breathing time" to repair DNA damage
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