Recombinational DNA repair and human disease

Larry H. Thompson, David Schild

Research output: Contribution to journalArticle

334 Citations (Scopus)

Abstract

We review the genes and proteins related to the homologous recombinational repair (HRR) pathway that are implicated in cancer through either genetic disorders that predispose to cancer through chromosome instability or the occurrence of somatic mutations that contribute to carcinogenesis. Ataxia telangiectasia (AT), Nijmegen breakage syndrome (NBS), and an ataxia-like disorder (ATLD), are chromosome instability disorders that are defective in the ataxia telangiectasia mutated (ATM), NBS, and Mre11 genes, respectively. These genes are critical in maintaining cellular resistance to ionizing radiation (IR), which kills largely by the production of double-strand breaks (DSBs). Bloom syndrome involves a defect in the BLM helicase, which seems to play a role in restarting DNA replication forks that are blocked at lesions, thereby promoting chromosome stability. The Werner syndrome gene (WRN) helicase, another member of the RecQ family like BLM, has very recently been found to help mediate homologous recombination. Fanconi anemia (FA) is a genetically complex chromosomal instability disorder involving seven or more genes, one of which is BRCA2. FA may be at least partially caused by the aberrant production of reactive oxidative species. The breast cancer-associated BRCA1 and BRCA2 proteins are strongly implicated in HRR; BRCA2 associates with Rad51 and appears to regulate its activity. We discuss in detail the phenotypes of the various mutant cell lines and the signaling pathways mediated by the ATM kinase. ATM's phosphorylation targets can be grouped into oxidative stress-mediated transcriptional changes, cell cycle checkpoints, and recombinational repair. We present the DNA damage response pathways by using the DSB as the prototype lesion, whose incorrect repair can initiate and augment karyotypic abnormalities.

Original languageEnglish (US)
Pages (from-to)49-78
Number of pages30
JournalMutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
Volume509
Issue number1-2
DOIs
StatePublished - Nov 30 2002
Externally publishedYes

Fingerprint

Recombinational DNA Repair
Chromosomal Instability
Ataxia Telangiectasia
Chromosome Disorders
Fanconi Anemia
Genes
BRCA2 Protein
Nijmegen Breakage Syndrome
BRCA1 Protein
Bloom Syndrome
Werner Syndrome
Inborn Genetic Diseases
Homologous Recombination
Ataxia
Cell Cycle Checkpoints
Ionizing Radiation
DNA Replication
DNA Damage
Neoplasms
Carcinogenesis

Keywords

  • Ataxia telangiectasia
  • Bloom syndrome
  • BRCA1
  • BRCA2
  • Chromosomal instability
  • Fanconi anemia
  • Werner syndrome

ASJC Scopus subject areas

  • Health, Toxicology and Mutagenesis
  • Molecular Biology

Cite this

Recombinational DNA repair and human disease. / Thompson, Larry H.; Schild, David.

In: Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis, Vol. 509, No. 1-2, 30.11.2002, p. 49-78.

Research output: Contribution to journalArticle

Thompson, Larry H. ; Schild, David. / Recombinational DNA repair and human disease. In: Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis. 2002 ; Vol. 509, No. 1-2. pp. 49-78.
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