DNA helicases, genomic instability, and human genetic disease

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 requir ed, including DNA replication, DNA repair and recombination, and transcript ion of RNA. Defects in helicases functioning in one or more of these proces ses can result in characteristic human genetic disorders in which genomic i nstability and predisposition to cancer are common features. So far, differ ent 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 RECQLA can result in Bloom syndrome, Werner syndrome, and Rothmund-Thomson syndrom e, respectively. Because XPB and XPD function in both nucleotide excision r epair and transcription initiation, the cellular phenotypes associated with a deficiency of each one of them include failure to repair mutagenic DNA l esions and defects in the recovery of RNA transcription after UV irradiatio n. 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 r eplication fork has become stalled. The genomic instability associated with mutations in the RecQ-like genes includes spontaneous chromosome instabili ty and elevated mutation rates. Mouse models for nearly all of these entiti es have been developed, and these should help explain the widely different clinical features that are associated with helicase mutations.