Abstract
Genomic disorders are a clinically diverse group of conditions caused by gain, loss or re-orientation of a genomic region containing dosage-sensitive genes. One class of genomic disorder is caused by hemizygous deletions resulting in haploinsufficiency of a single or, more usually, several genes. For example, the heterozygous contiguous gene deletion on chromosome 22q11.2 causing DiGeorge syndrome involves at least 20-30 genes. Determining how the copy number variation (CNV) affects human variation and contributes to the aetiology and progression of various genomic disorders represents important questions for the future. Here, I will discuss the functional significance of one form of CNV, haploinsufficiency (i.e. loss of a gene copy), of DNA damage response components and its association with certain genomic disorders. There is increasing evidence that haploinsufficiency for certain genes encoding key players in the cells response to DNA damage, particularly those of the Ataxia Telangiectasia and Rad3-related (ATR)-pathway, has a functional impact. I will review this evidence and present examples of some well known clinically similar genomic disorders that have recently been shown to be defective in the ATR-dependent DNA damage response. Finally, I will discuss the potential implications of a haploinsufficiency-induced defective DNA damage response for the clinical management of certain human genomic disorders.
Highlights
It has long been appreciated that changes in gene copy number are associated with phenotypes in humans
The widespread use of a-CGH has facilitated the description of several novel genomic disorders and aided in the detailed genetic characterisation of known genomic disorders
Nijmegen Breakage Syndrome (NBS) has been described as an A-T-like disorder as cell lines from both conditions exhibit radio-sensitivity and similar cell cycle checkpoint defects in response to double strand breaks (DSBs)
Summary
It has long been appreciated that changes in gene copy number are associated with phenotypes in humans. The Mre11/Rad50/NBS1 complex, the Rad17/Rfc and Rad9/Rad1/Hus complexes are recruited to the site of damage independently of ATR/ATRIP and are phosphorylated by ATR [25, 26]. Retention of these complexes facilitates ATR’s ability to phosphorylate downstream substrates including Brca, p53 and its effector kinase Chk1 [15]. There is a large amount of functional overlap between ATM and ATR Both kinase’s phosphorylate mainly the same substrates in response to DNA damage (e.g. Mre11/ Rad50/NBS1 complex, p53, Brca). Mutations in ATR result in Seckel syndrome, a disorder characterised by microcephaly and growth retardation [31, 32]
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