DNA Damage Processing Defects and Disease

Abstract

Inherited defects in DNA repair or the processing of DNA damage can lead to disease. Both autosomal recessive and autosomal dominant modes of inheritance are represented. The diseases as a group are characterized by genomic instability, with eventual appearance of cancer. The inherited defects frequently have a specific DNA damage sensitivity, with cells from affected individuals showing normal resistance to other genotoxic agents. The known defects are subtle alterations in transcription, replication, or recombination, with alternate pathways of processing permitting cellular viability. Distinct diseases may arise from different mutations in one gene; thus, clinical phenotypes may reflect the loss of different partial functions of a gene. The findings indicate that partial defects in transcription or recombination lead to genomic instability, cancer, and characteristic disease phenotypes.

Fanconi anaemia

“…As the BRCA1 associated genome surveillance complex (BASC) includes DNA damage repair proteins such as ATM, NBS1, MRE11, BLM, and MSH2 (these genes are mutated in ataxia-telangiectasia, Nijmegen breakage syndrome, AT-like disorder, Bloom's syndrome, and HNPCC respectively), FA may be linked at a molecular level to these other DNA damage repair disorders. [98][99][100] The intriguing discovery that FANCD1 and possibly also FANCB are in fact BRCA2 indicates that the pathways involved in breast cancer susceptibility and FA are interconnected at more than one level. 13 16 THE FA FUNCTIONAL PATHWAY DNA repair in the FA cell The exact mechanisms that lead to disruption of DNA repair in FA cells remain disputed.…”

Topo IIIα and BLM Act within the Fanconi Anemia Pathway in Response to DNA-Crosslinking Agents

“…These observations demonstrate that the association of BLM and Topoisomerase III ␣ with Fanconi proteins is a functional one, delineating a BLM-Topoisomerase III ␣ -Fanconi pathway that is critical for suppression of chromosome radial formation. Copyright © 2009 S. Karger AG, Basel Bloom syndrome (BS) is a rare recessive disorder characterized by growth retardation, immunodeficiency, photosensitivity, and an increased incidence of cancers including leukemias, lymphomas, and carcinomas [German, 1995;Moses, 2001;Hickson, 2003]. Cells from BS patients manifest chromosomal aberrations, including sister chromatid exchanges (SCEs) [Chaganti et al, 1974] which are used for clinical diagnosis, and increased radials.…”

“…It manifests growth abnormalities, deficiencies in all blood cell lineages, and an increased risk of malignancies [Moses, 2001;D'Andrea and Grompe, 2003]. FA cells show increased cellular sensitivity to agents that form DNA interstrand crosslinks (ICLs), as manifested by chromosomal breaks and radials [Schroeder et al, 1964].…”

Inferring Gene Network from Candidate SNP Association Studies Using a Bayesian Graphical Model: Application to a Breast Cancer Case-Control Study from Ontario

“…In this paper, our gene network analysis focuses on SNPs implicated in DNA repair processes, which have long been known to be associated with certain inherited diseases such as premature aging syndromes and cancer [17][18][19] . To date, approximately 100 genes functioning within 5 DNA damage recognition and repair pathways have been identified [20,21] .…”