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TP53
tumor protein p53
TP53 encodes tumour protein p53, a critical regulator of cell division and DNA repair often called the guardian of the genome. The TP53 gene provides instructions for making the p53 protein, which controls whether cells with damaged DNA should be repaired or eliminated.
TP53 is located on the short (p) arm of chromosome 17, at band 17p13.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The TP53 gene encodes tumour protein p53, a transcription factor that acts as a tumour suppressor by regulating cellular responses to DNA damage and stress. Located on chromosome 17, TP53 produces a protein of 393 amino acids that monitors genomic integrity and determines cell fate when DNA damage occurs. When cellular DNA is harmed by radiation, toxic chemicals, or other insults, p53 either activates repair pathways or triggers programmed cell death to prevent damaged cells from proliferating.
Inherited pathogenic variants in TP53 cause Li-Fraumeni syndrome, an autosomal dominant condition characterised by markedly increased lifetime risk of multiple cancer types, including breast cancer, soft tissue sarcomas, and bone cancers. Somatic mutations in TP53 are also among the most common alterations found in human cancers, reflecting the gene's central role in preventing uncontrolled cell growth. The protein's function is so fundamental to cancer prevention that it has been termed the guardian of the genome.
What the gene does
Tumour protein p53 functions primarily as a sequence-specific transcription factor that binds directly to DNA in the cell nucleus. When DNA damage is detected, p53 becomes activated and regulates the expression of genes involved in cell-cycle arrest, DNA repair, and apoptosis. By halting cell division temporarily, p53 provides time for repair machinery to correct damaged DNA before replication occurs. If the damage proves irreparable, p53 initiates apoptotic pathways to eliminate the compromised cell, thereby preventing the propagation of potentially cancerous mutations.
The protein achieves these effects through both transcription-dependent and transcription-independent mechanisms. As a transcription factor, p53 activates genes encoding cell-cycle checkpoint proteins and pro-apoptotic factors. The protein also participates in DNA repair coordination by interacting with repair complexes and modulating their activity. This dual capacity to pause proliferation and orchestrate repair responses makes p53 essential for maintaining genomic stability across cell divisions. Without functional p53, cells with mutated DNA can continue dividing unchecked, greatly increasing the likelihood of tumour development.
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Chromosome location
TP53 is located on the short arm of chromosome 17 at position 13.1 (17p13.1). The gene spans approximately 20 kilobases and contains 11 exons that encode the 393-amino-acid p53 protein. This chromosomal region is critical for tumour suppression, and deletions or mutations affecting 17p13.1 are frequently observed in various cancers.
Protein structure
The p53 protein comprises several functionally distinct domains that enable its tumour-suppressor activities. The N-terminal region contains the transcription activation domain, subdivided into TADI (amino acids 17-25) and TADII (amino acids 48-56), which recruits transcriptional co-activators. A disordered region spans amino acids 50-96, contributing to regulatory flexibility. The central DNA-binding domain (amino acids 102-292) is the most highly conserved region and directly contacts DNA sequences to regulate target gene expression. Within this domain, amino acids 273-280 specifically interact with DNA.
The protein also features multiple interaction regions that mediate partnerships with regulatory proteins. The region encompassing amino acids 1-320 facilitates interaction with CCAR2, whilst amino acids 1-83 bind HRMT1L2. Amino acids 66-110 interact with WWOX, and the region from amino acids 100-370 engages HIPK1. A segment from amino acids 100-300 is required for interaction with ZNF385A, and amino acids 113-236 are necessary for FBXO42 binding. The region spanning amino acids 116-292 interacts with AXIN1, amino acids 241-248 bind the 53BP2 SH3 domain, and amino acids 256-294 engage E4F1. This extensive interaction network enables p53 to coordinate diverse cellular responses to stress.
Key variants
Pathogenic variants in TP53 include missense changes, nonsense mutations, frameshift insertions or deletions, and splice-site alterations. Most disease-causing variants cluster within the DNA-binding domain, impairing the protein's ability to recognise and bind target gene sequences. Inherited variants follow an autosomal dominant pattern, meaning a single altered copy is sufficient to substantially increase cancer risk. Somatic TP53 mutations are among the most frequently identified genetic changes in human cancers, occurring in more than half of all tumour types.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1009C>T | p.Arg337Cys | Pathogenic | ★★★☆ | Hereditary cancer-predisposing syndrome |
c.1025G>C | p.Arg342Pro | Pathogenic | ★★★☆ | Li-Fraumeni syndrome |
c.1040C>A | p.Ala347Asp | Pathogenic | ★★★☆ | not specified |
c.318C>G | p.Ser106Arg | Pathogenic | ★★★☆ | not specified |
c.329G>C | p.Arg110Pro | Pathogenic | ★★★☆ | Hereditary cancer-predisposing syndrome |
c.329G>T | p.Arg110Leu | Pathogenic | ★★★☆ | Li-Fraumeni syndrome |
c.332T>A | p.Leu111Gln | Pathogenic | ★★★☆ | Li-Fraumeni syndrome |
c.332T>C | p.Leu111Pro | Pathogenic | ★★★☆ | Ovarian neoplasm |
c.332T>G | p.Leu111Arg | Pathogenic | ★★★☆ | Li-Fraumeni syndrome |
c.372C>A | p.Cys124Ter | Pathogenic | ★★★☆ | Li-Fraumeni syndrome |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Inherited pathogenic variants in TP53 cause Li-Fraumeni syndrome, an autosomal dominant cancer predisposition condition associated with elevated lifetime risk of multiple cancer types. Individuals with Li-Fraumeni syndrome face increased susceptibility to breast cancer, soft tissue sarcomas, osteosarcomas, brain tumours, and adrenocortical carcinoma, often with onset at younger ages than observed in the general population. Somatic TP53 mosaicism, in which mutations arise after conception and are present in only a subset of cells, has also been described and may present with features overlapping those of classical Li-Fraumeni syndrome.
Inheritance pattern
Conditions caused by pathogenic TP53 variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
TP53 appears on multiple NHS Genomic Medicine Service PanelApp panels with green (high-evidence) classification, reflecting its well-established role in cancer predisposition. The gene is included in panels for Li-Fraumeni syndrome (R216), familial breast cancer, childhood solid tumours, sarcoma susceptibility, and inherited predisposition to acute myeloid leukaemia (R347), among others. TP53 is also listed on the ACMG Secondary Findings v3.2 list as a Tier 1 actionable gene, meaning variants may be reported incidentally during clinical genomic testing due to available risk-reduction strategies.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is Li-Fraumeni syndrome?
Li-Fraumeni syndrome is an inherited condition caused by pathogenic variants in TP53 that substantially increases the lifetime risk of multiple cancer types, including breast cancer, sarcomas, brain tumours, and adrenocortical carcinoma. Cancers often develop at younger ages than in the general population, and affected individuals may develop more than one primary tumour during their lifetime.
Why is p53 called the guardian of the genome?
The p53 protein earned this designation because it monitors DNA integrity and prevents cells with damaged genetic material from dividing. When DNA damage is detected, p53 either activates repair mechanisms or triggers cell death, thereby protecting the genome from accumulating mutations that could lead to cancer.
Are TP53 variants common in cancer?
Somatic (non-inherited) TP53 mutations are among the most frequent genetic alterations in human cancers, found in more than half of all tumour types. These acquired mutations arise in individual cells and are not passed to offspring, in contrast to the inherited variants that cause Li-Fraumeni syndrome.
References
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- Masica DL, Li S, Douville C. Predicting survival in head and neck squamous cell carcinoma from TP53 mutation. Human genetics. 2015. PMID: 25108461
- Toss A, Tomasello C, Razzaboni E. Hereditary ovarian cancer: not only BRCA 1 and 2 genes. BioMed research international. 2015. PMID: 26075229
- Silwal-Pandit L, Vollan HK, Chin SF. TP53 mutation spectrum in breast cancer is subtype specific and has distinct prognostic relevance. Clinical cancer research : an official journal of the American Association for Cancer Research. 2014. PMID: 24803582
- Damineni S, Rao VR, Kumar S. Germline mutations of TP53 gene in breast cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. 2014. PMID: 24929325
- Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014. PMID: 25079552
- Merino D, Malkin D. p53 and hereditary cancer. Sub-cellular biochemistry. 2014. PMID: 25201186
- Loyo M, Li RJ, Bettegowda C. Lessons learned from next-generation sequencing in head and neck cancer. Head & neck. 2013. PMID: 22907887
- Masciari S, Dillon DA, Rath M. Breast cancer phenotype in women with TP53 germline mutations: a Li-Fraumeni syndrome consortium effort. Breast cancer research and treatment. 2012. PMID: 22392042
- Olivier M, Hollstein M, Hainaut P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harbor perspectives in biology. 2010. PMID: 20182602
- Ruijs MW, Verhoef S, Rookus MA. TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes. Journal of medical genetics. 2010. PMID: 20522432
- Olivier M, Langerød A, Carrieri P. The clinical value of somatic TP53 gene mutations in 1,794 patients with breast cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2006. PMID: 16489069
- Adam MP, Bick S, Mirzaa GM. Li-Fraumeni Syndrome. 1993. PMID: 20301488