Caretakers and Gatekeepers


Oncogenes and tumour suppressor genes are considered genes whose alterations, including intragenic mutations, chromosomal deletions and loss of expression, are involved in tumour onset and progression, by promoting abnormal growth and cell division. Different critical cell processes, including apoptosis and cell cycle, differentiation, signal transduction, cell adhesion, maintenance of genomic integrity and DNA (deoxyribonucleic acid) damage repair, are regulated by tumour suppressor genes. It has been generally accepted that tumour suppressor genes responsible for familial cancer syndromes can be divided into two major categories, known as caretakers and gatekeepers. Inactivation of both genes contributes directly to cancer development and progression. Caretakers are genes that control the maintenance of the genetic information integrity in each cell, while gatekeepers are those genes which directly regulate tumour growth, codifying for proteins which either stimulate or inhibit proliferation, differentiation or apoptosis. Gatekeeper and caretaker genes of major interest include APC, RB1, CDKN2A, TP53, BRCA genes.

Key Concepts

  • Tumour suppressor genes responsible for familial cancer syndromes can be divided into two major categories, known as caretakers and gatekeepers.
  • Caretaker genes are involved in the maintenance of the genome stability and include genes implicated in DNA repair.
  • Gatekeeper genes inhibit cell growth or induce apoptosis.
  • The APC gatekeeper is the susceptibility gene responsible for familial adenomatous polyposis (FAP).
  • The RB1 mutations are responsible for 60% of non‐hereditary and unilateral retinoblastomas and 40% of hereditary forms.
  • Germline CDKN2A mutations have been described in 25–40% of melanoma‐prone families from several countries.
  • The p53 mutations may accumulate at very high levels in tumours and gain new functions (gain‐of‐function) to promote tumorigenesis and malignant progression.
  • BRCA1 and BRCA2 are two high‐penetrance caretaker genes responsible for hereditary breast and ovarian cancer.
  • PARP1 is an enzyme that regulates several proteins involved in DNA repair and maintenance of genome integrity.

Keywords: gatekeeper genes; caretaker genes; tumour suppressor genes; cell cycle; hereditary syndromes

Figure 1. Caretaker and gatekeeper pathways.
Figure 2. PARP (poly‐ADP ribosome polymerase) activity in DNA (deoxyribonucleic acid) repair mechanisms.


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Fanale, Daniele, Maragliano, Rossella, Bazan, Viviana, and Russo, Antonio(Sep 2017) Caretakers and Gatekeepers. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0006048.pub2]