DNA repair, genome stability and cancer: a historical perspective

  title={DNA repair, genome stability and cancer: a historical perspective},
  author={Penny A. Jeggo and Laurence H. Pearl and Antony M. Carr},
  journal={Nature Reviews Cancer},
The multistep process of cancer progresses over many years. The prevention of mutations by DNA repair pathways led to an early appreciation of a role for repair in cancer avoidance. However, the broader role of the DNA damage response (DDR) emerged more slowly. In this Timeline article, we reflect on how our understanding of the steps leading to cancer developed, focusing on the role of the DDR. We also consider how our current knowledge can be exploited for cancer therapy. 

DNA repair defects and implications for immunotherapy.

This observation has paved the way for further research investigating other sources of genomic instability that may serve as biomarkers to select patients for immunotherapy.

Nucleotide Excision Repair: From Neurodegeneration to Cancer.

Nucleotide Excision Repair pathway, the causative role of its components in disease-related pathology and recent technological achievements that decipher mutational landscapes and may facilitate pathological classification and personalized therapy are discussed.

Oncometabolites as Regulators of DNA Damage Response and Repair.

DNA Damage Response Pathways in Cancer Predisposition and Metastasis

The current chapter discusses the role of various DNA damage repair pathways along with their genes in cancer predisposition and metastasis.

DNA damage repair: historical perspectives, mechanistic pathways and clinical translation for targeted cancer therapy

Two hypotheses are suggested, namely “environmental gear selection” to describe DNA damage repair pathway evolution, and “DNA damage baseline drift”, which may play a magnified role in mediating repair during cancer treatment, which shed new light on targeted cancer therapy and also promote the development of new research direction and new overcoming strategies for patients.

Proteins from the DNA Damage Response: Regulation, Dysfunction, and Anticancer Strategies

These new types of treatments are adapted to the different types of tumor sensitivity and could benefit from a combination of therapies to ensure maximal efficiency.

Alternative Non-Homologous End-Joining: Error-Prone DNA Repair as Cancer’s Achilles’ Heel

The role of the error-prone DNA repair, named Alternative Non-Homologous End Joining (Alt-NHEJ), as inducer of genomic instability and as a potential therapeutic target is discussed for precision oncology.

Fight to the bitter end: DNA repair and aging

Repurposing DNA repair factors to eradicate tumor cells upon radiotherapy.

The impact of targeting cancer-specific aberrations in the DDR as a treatment strategy to improve the efficacy of RT is described and the current roadblocks and future prospects of these approaches are addressed.

The DNA damage response in immunotherapy and radiation




The evolution of diverse biological responses to DNA damage: insights from yeast and p53

It is proposed that the diversity of responses to ionizing radiation in mammalian cells is possible because of the addition of a new regulatory control module involving the tumour-suppressor gene p53.

Therapeutic opportunities within the DNA damage response

An in-depth analysis of the function, role and therapeutic potential of 450 expert-curated human DDR genes is presented, and systematic computational analysis is applied to identify DDR proteins that are amenable to modulation by small molecules, highlighting potential novel therapeutic targets.

An Oncogene-Induced DNA Damage Model for Cancer Development

Oncogene-induced DNA damage may explain two key features of cancer: genomic instability and the high frequency of p53 mutations.

DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis

It is shown that in clinical specimens from different stages of human tumours of the urinary bladder, breast, lung and colon, the early precursor lesions commonly express markers of an activated DNA damage response.

A brief history of the DNA repair field

The history of the repair of damaged DNA can be traced to the mid-1930s. Since then multiple DNA repair mechanisms, as well as other biological responses to DNA damage, have been discovered and their

Mechanisms of resistance to therapies targeting BRCA-mutant cancers

In this Perspective, multiple potential resistance mechanisms have been identified and their relevance to the development of selective therapies for BRCA-deficient cancers are discussed.

Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions

It is proposed that, from its earliest stages, cancer development is associated with DNA replication stress, which leads to DNA double-strand breaks, genomic instability and selective pressure for p53 mutations.

The Croonian Lecture, 1996: endogenous damage to DNA.

  • T. Lindahl
  • Biology
    Philosophical transactions of the Royal Society of London. Series B, Biological sciences
  • 1996
Although DNA is the carrier of stable genetic information, this giant molecule exhibits slow turnover in cells as a consequence of endogenous damage, some forms of endogenous DNA damage still cause mutagenic alterations and may result in human disease.

How the fanconi anemia pathway guards the genome.

The current understanding of how the Fanconi Anemia pathway components participate in DNA repair is reviewed and the mechanisms that regulate this pathway to ensure timely, efficient, and correct restoration of chromosomal integrity are discussed.

The relationship of DNA methylation to cancer.

It is too early to consider involvement of purely epigenetic processes as proven, but there is strong evidence that DNA methylation is not a neutral bystander in carcinogenesis, but actively contributes to the process.