Box 1 | Genomic instability syndromes

Genetic defects that affect specific DNA damage response pathways lead to syndromes that combine various degrees of tissue degeneration, growth and developmental retardation, premature signs of ageing, chromosomal instability, sensitivity to the corresponding DNA-damaging agents and cancer predisposition. The prominent genomic instability syndromes^{3, 5, 6, 7, 8} listed below are all autosomal recessive and represent defects in the main damage-response pathways, each of which is activated by a different class of damaging agent. Three diseases — xeroderma pigmentosum, Cockayne's syndrome and trichothiodystrophy — are associated with defects in the nucleotide-excision-repair (NER) pathway that deals with bulky, helix-distorting DNA lesions such as those inflicted by ultraviolet-light (UV) radiation and certain chemicals.

Xeroderma pigmentosum (XP)

XP patients are extremely sensitive to the UV-light component of sunlight and show accelerated ageing of the skin and a striking tendency to skin cancers. XP is genetically heterogeneous. Its classical form entails defects in various proteins that act together in the nucleotide-excision-repair (NER) pathway. NER has a global repair arm and a transcription-coupled repair arm, and one or both might be defective in different XP patients. Some XP proteins are involved in DNA repair and are also part of the transcription complex TFIIH, and one of them is a DNA polymerase that is responsible for trans-lesion DNA synthesis.

Cockayne's syndrome

This UV-light sensitivity syndrome is characterized by striking dwarfism and skeletal malformations, severe mental retardation, deafness and photosensitivity, but no apparent cancer predisposition. The defective proteins are involved in transcription-coupled repair of DNA damage that is induced by UV light and probably oxidative DNA damage.

Trichothiodystrophy (TTD)

This rare disease is characterized by brittle hair, dry skin, dysmorphic face, mental retardation and a certain degree of photosensitivity. The mutations that are responsible for this occur in a specific region of the XPB and XPD genes that encode DNA helicases involved in transcription — other mutations in these genes cause XP or Cockayne's syndrome. This is an interesting example of different mutations within the same gene leading to different phenotypic outcomes.

Bloom's syndrome (BS)

BS patients have short stature, sun sensitivity, facial erythema, immunonodeficiency, decreased fertility and a predisposition to various cancers. BS cells show striking elevation of spontaneous sister-chromatid exchanges, chromosomal breakage and mild sensitivity to various DNA-damaging agents. The defective protein, BLM, is a DNA helicase that resembles the bacterial recQ protein, which probably participates in homologous recombination repair and repair of damage that occurs at stalled replication forks.

Werner's syndrome (WS)

WS is characterized primarily by accelerated ageing, and also by a tendency for diabetes, delayed sexual development, chromosomal instability and a predisposition to various cancers. WS cells show chromosomal instability and are hypersensitive to camptothecin — an inhibitor of type I DNA topoisomerase — and certain DNA alkylating and crosslinking agents. Of note, both BS and WS cells are hypersensitive to hydroxyurea-induced apoptotic killing. The defective protein — WRN — is another DNA helicase of the recQ-like family with a unique 3'5' exonuclease activity.

Rothmund–Thompson syndrome (RTS)

RTS patients are recognized by their patchy skin coloration, stunted growth, skeletal abnormalities, early cataracts, accelerated ageing, chromosomal instability and cancer predisposition. The culprit gene — RECQL4 — encodes yet another recQ-like DNA helicase, the role of which in the DNA-damage response is unclear.

Fanconi's anemia (FA)

The main characteristics of FA are bone-marrow depletion, which leads to aplastic anaemia (insufficient formation of all blood cell types), skeletal malformations, deformities of various internal organs, reduced fertility, cutaneous abnormalities and marked predisposition to myeloid leukaemias and squamous-cell carcinomas. FA cells show characteristic chromosomal aberrations and sensitivity to DNA crosslinking and DNA-breaking agents. The disease is genetically heterogeneous, with mutations affecting eight different 'FA genes', the products of which interact with each other and with various components of the DNA-damage response systems, such as BRCA1 and ATM (see text and recent review by D'Andrea and Grompe¹⁶⁷). Recently, it was found that homozygosity for certain BRCA2 mutations is responsible for one form of FA¹⁶⁸.

Others

Additional genome instability syndromes are ataxia-telangiectasia (A-T), Nijmegen breakage syndrome (NBS) and ataxia-telangiectasia-like disease (ATLD); these are discussed in detail in the main text.