Paper I
Question
Role of P53 in gene in tumor suppression
Answer
TP53 is often called the “guardian of the genome” — it is the most commonly mutated gene in human cancers.
Normal function
- In response to DNA damage or cellular stress, p53 protein levels rise and activate transcription of target genes that:
- Arrest the cell cycle at the G1/S checkpoint (via p21, a CDK inhibitor), allowing time for DNA repair
- Promote DNA repair
- Induce apoptosis (via BAX and other pro-apoptotic genes) if the damage is irreparable, eliminating the potentially dangerous mutated cell
Mechanism of tumour suppression
- By halting the cell cycle or eliminating cells with damaged DNA, p53 prevents the propagation of mutations to daughter cells
- It is a classic “gatekeeper” tumour suppressor gene, requiring loss of function of both alleles (Knudson’s two-hit hypothesis) for its tumour-suppressive effect to be lost
Consequence of TP53 mutation/loss
- Cells with DNA damage are no longer arrested or eliminated, allowing accumulation of further mutations and genomic instability, promoting malignant transformation
- Germline TP53 mutations cause Li-Fraumeni syndrome — a familial cancer predisposition syndrome with multiple early-onset malignancies (sarcomas, breast cancer, brain tumours, leukaemia)
- Somatic TP53 mutations are found in the majority of sporadic human cancers