22 DNA Helicases and Human Disease

Abstract

Helicases are motor proteins that utilize the energy derived from the hydrolysis of nucleoside triphosphates (NTP/dNTP) to disrupt hydrogen-bond interactions in double- or multi-stranded DNA and RNA. All known helicases are recognized to have at least two intrinsic enzymatic activities: (1) NTP/dNTP-dependent nucleic acid unwinding and (2) DNA/RNA-dependent NTP/dNTP hydrolysis. Unwinding of DNA and RNA, with the generation of single-stranded nucleic acids, is essential for numerous cellular transactions, including DNA replication, repair, and recombination, as well as RNA splicing, transcription, and translation. Helicases therefore are ubiquitous, key players in several aspects of nucleic acid metabolism. The importance of helicases can be gleaned from the fact that, to date, 14 different DNA helicases have been identified in bacteria, 15 in yeast, and 25 in human cells (for a compilation of known helicases, see Tuteja and Tuteja 2004). In addition, mutations in genes encoding DNA helicases have been demonstrated in several inherited human diseases. The fact that these diseases are rare also emphasizes the essentiality of DNA helicases in cellular metabolism. In this chapter, we consider the different helicases, the proposed mechanisms for strand separation, their roles in cellular metabolism, and finally, the human diseases associated with mutations in specific DNA helicases.

HELICASE CLASSIFICATION
Helicases are frequently classified by the presence of signature sequence motifs, substrate specificities, or the directionality of unwinding. Four superfamilies have been defined on the basis of the number and sequence of helicase motifs they encode (Gorbalenya and Koonin 1993). Although this number is variable, all helicases contain...