DNA Helicases, Genomic Instability, and Human Genetic Disease

Abstract

DNA helicases are a highly conserved group of enzymes that unwind DNA. They function in all processes in which access to single-stranded DNA is required, including DNA replication, DNA repair and recombination, and transcription of RNA. Defects in helicases functioning in one or more of these processes can result in characteristic human genetic disorders in which genomic instability and predisposition to cancer are common features. So far, different helicase genes have been found mutated in six such disorders. Mutations in XPB and XPD can result in xeroderma pigmentosum, Cockayne syndrome, or trichothiodystrophy. Mutations in the RecQ-like genes BLM, WRN, and RECQL4 can result in Bloom syndrome, Werner syndrome, and Rothmund-Thomson syndrome, respectively. Because XPB and XPD function in both nucleotide excision repair and transcription initiation, the cellular phenotypes associated with a deficiency of each one of them include failure to repair mutagenic DNA lesions and defects in the recovery of RNA transcription after UV irradiation. The functions of the RecQ-like genes are unknown; however, a growing body of evidence points to a function in restarting DNA replication after the replication fork has become stalled. The genomic instability associated with mutations in the RecQ-like genes includes spontaneous chromosome instability and elevated mutation rates. Mouse models for nearly all of these entities have been developed, and these should help explain the widely different clinical features that are associated with helicase mutations.

Aging, tumor suppression and cancer: high wire-act!

“…Thus, cell division in adult somatic tissues appears to put organisms at risk for developing cancer. This is not surprising, given that we now know that DNA replication puts cells at endanger for acquiring and fixing mutations (Kunkel and Bebenek, 2000;van Brabant et al, 2000;Friedberg et al, 2002;Thompson and Schild, 2002), and that somatic mutations are a major cause of cancer (Bishop, 1995;Simpson and Camargo, 1998;Gray and Collins, 2000;Knudson, 2000).…”

DNA Repair and Tumorigenesis: Lessons from Hereditary Cancer Syndromes

“…82 These biochemical activities suggested that BLM might act on a replication fork that was stalled and reversed by a DNA lesion (forming a Holliday Junction; ref. 84). Following lesion repair, the BLM helicase was proposed to unwind the four-strand junction starting at the single open-end to restore a functional replication fork.…”

DNA double-strand break repair and development

“…Defects in a variety of DNA repair pathways result in diseases characterized by a range of distinct phenotypes. For example, defects in DNA helicases (for example, Bloom syndrome) can result in dwarfism and increased sister-chromatid exchange, defects in the repair of DNA crosslinks (Fanconi anemia) is associated with diverse congenital abnormalities and bone marrow failure, while defects in the repair of UV damage (for example, xeroderma pigmentosum) can lead to sun-induced skin and eye lesions, and all of these DNA repair syndromes predispose to cancer (van Brabant et al, 2000;Hoeijmakers, 2001;D'Andrea, 2003;Cleaver, 2005). Human syndromes also result from defective responses to DNA double-strand breaks (DSBs), such as ataxia telangiectasia (AT) and Nijmegen breakage syndrome (NBS) that show striking effects in the nervous and immune systems and exhibit cancer predisposition (McKinnon and Caldecott, 2007).…”