DNA helicases associated with genetic instability, cancer, and aging

Abstract

DNA helicases have essential roles in the maintenance of genomic -stability. They have achieved even greater prominence with the discovery that mutations in human helicase genes are responsible for a variety of genetic disorders and are associated with tumorigenesis. A number of missense mutations in human helicase genes are linked to chromosomal instability diseases characterized by age-related disease or associated with cancer, providing incentive for the characterization of molecular defects underlying aberrant cellular phenotypes. In this chapter, we discuss some examples of clinically relevant missense mutations in various human DNA helicases, particularly those of the Iron-Sulfur cluster and RecQ families. Clinically relevant mutations in the XPD helicase can lead to Xeroderma pigmentosum, Cockayne's syndrome, Trichothiodystrophy, or COFS syndrome. FANCJ mutations are associated with Fanconi anemia or breast cancer. Mutations of the Fe-S helicase ChlR1 (DDX11) are linked to Warsaw Breakage syndrome. Mutations in the RecQ helicases BLM and WRN are linked to the cancer-prone disorder Bloom's syndrome and premature aging condition Werner syndrome, respectively. RECQL4 mutations can lead to Rothmund-Thomson syndrome, Baller-Gerold syndrome, or RAPADILINO. Mutations in the Twinkle mitochondrial helicase are responsible for several neuromuscular degenerative disorders. We will discuss some insights gained from biochemical and genetic studies of helicase variants, and highlight some hot areas of helicase research based on recent developments.

Fig. 6.1

Depending on their specialty, DNA helicases use the energy of ATP hydrolysis to perform multiple functions. (a) A DNA helicase can disrupt noncovalent hydrogen bonds between complementary strands of the DNA double helix to form transient single-stranded DNA tracts. (b) A DNA helicase can strip proteins (e.g., Rad51) off DNA to regulate HR. (c) A DNA helicase can resolve alternate DNA structures (e.g., G-quadruplex) to enable smooth progression of the replication fork

Fig. 6.2

Clinically relevant missense mutations in XPD helicase responsible for Xeroderma pigmentosum, Xeroderma pigmentosum combined with Cockayne syndrome, Trichothiodystrophy, and COFS Syndrome. See text for details. For discussion of XPD mutations and genetic heterogeneity, see ref. [13]. XPD-D681N mutation is associated with XP and COFS syndrome

Fig. 6.3

Clinically relevant missense mutations in FANCJ helicase responsible for Fanconi Anemia complementation group J and associated with breast cancer. See text for details. For a comprehensive listing of FANCJ mutations, see The Rockefeller University-Fanconi anemia mutation database www.rockefeller.edu/fanconi/mutate; also see ref. [18]

Fig. 6.4

An FA complementation group J patient mutation (A349P) in the conserved Fe-S domain uncouples DNA ATPase and translocase activities from strand separation (helicase) activity. (a) FANCJ protein with the conserved helicase core domain, key protein interaction domains, and the Fe-S cluster. The conserved helicase motifs are indicated by yellow boxes, and the protein interaction domains for MLH1 and BRCA1 are shown by aqua green and blue boxes, respectively. The expanded Fe-S domain shows the locations for conserved cysteine residues in orange, and the A349P missense mutation of a FANCJ patient in bold. (b) The purified recombinant FANCJ-A349P protein fails to couple ATPase and single-stranded DNA translocase activity to unwinding duplex DNA. See text and ref. [59] for details

Fig. 6.5

Clinically relevant missense mutations in BLM helicase responsible for Bloom’s syndrome. See text for details. For a comprehensive listing of BLM mutations, see The Bloom’s Syndrome Registry www.med.cornell.edu/bsr/; also see ref. [65]

Fig. 6.6

Clinically relevant missense mutations in RECQL4 helicase responsible for Rothmund-Thomson syndrome, Baller-Gerold syndrome, and RAPADILINO. See text for details. For comprehensive listing of RECQL4 mutations, see ref. [36]. RECQL4-R1021W is associated with both RTS and BGS

Fig. 6.7

Clinically relevant missense mutations in WRN helicase-nuclease responsible for Werner syndrome. See text for details. For a comprehensive listing of WRN mutations, see The International Registry of Werner Syndrome www.wernersyndrome.org; also see ref. [73]