Specialization among iron-sulfur cluster helicases to resolve G-quadruplex DNA structures that threaten genomic stability.
G-quadruplex (G4) DNA, an alternate structure formed by Hoogsteen hydrogen bonds between guanines in G-rich sequences, threatens genomic stability by perturbing normal DNA transactions including replication, repair, and transcription. A variety of G4 topologies (intra- and intermolecular) can form in vitro, but the molecular architecture and cellular factors influencing G4 landscape in vivo are not clear. Helicases that unwind structured DNA molecules are emerging as an important class of G4-resolving enzymes. The BRCA1-associated FANCJ helicase is among those helicases able to unwind G4 DNA in vitro, and FANCJ mutations are associated with breast cancer and linked to Fanconi anemia. FANCJ belongs to a conserved iron-sulfur (Fe S) cluster family of helicases important for genomic stability including XPD (nucleotide excision repair), DDX11 (sister chromatid cohesion), and RTEL (telomere metabolism), genetically linked to xeroderma pigmentosum/Cockayne syndrome, Warsaw breakage syndrome, and dyskeratosis congenita, respectively. To elucidate the role of FANCJ in genomic stability, its molecular functions in G4 metabolism were examined. FANCJ efficiently unwound in a kinetic and ATPase-dependent manner entropically favored unimolecular G4 DNA, whereas other Fe-S helicases tested did not. The G4-specific ligands Phen-DC3 or Phen-DC6 inhibited FANCJ helicase on unimolecular G4 ∼1000-fold better than bi- or tetramolecular G4 DNA. The G4 ligand telomestatin induced DNA damage in human cells deficient in FANCJ but not DDX11 or XPD. These findings suggest FANCJ is a specialized Fe-S cluster helicase that preserves chromosomal stability by unwinding unimolecular G4 DNA likely to form in transiently unwound single-stranded genomic regions.
From the Laboratory of Molecular Gerontology, NIA, National Institutes of Health, National Institutes of Health Biomedical Research Center, Baltimore, Maryland 21224.
Sanjay Kumar
SK
Bharti
Joshua A
JA
Sommers
Fourbears
F
George
Jochen
J
Kuper
Florian
F
Hamon
Kazuo
K
Shin-ya
Marie-Paule
MP
Teulade-Fichou
Caroline
C
Kisker
Robert M
RM
Brosh
D050976:Basic-Leucine Zipper Transcription Factors / Q000737:chemistry* / Q000235:genetics; D004247:DNA / Q000737:chemistry; D004265:DNA Helicases / Q000235:genetics; D004260:DNA Repair; D004261:DNA Replication; D004926:Escherichia coli / Q000378:metabolism; D051856:Fanconi Anemia Complementation Group Proteins / Q000737:chemistry* / Q000235:genetics; D054856:G-Quadruplexes; D005786:Gene Expression Regulation; D042822:Genomic Instability; D006147:Guanine / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D007506:Iron-Sulfur Proteins / Q000737:chemistry*; D008024:Ligands; D034622:RNA Interference; D011994:Recombinant Proteins / Q000737:chemistry; D013822:Thermoplasma / Q000378:metabolism
C102108:BACH1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D051856:Fanconi Anemia Complementation Group Proteins; D007506:Iron-Sulfur Proteins; D008024:Ligands; D011994:Recombinant Proteins; D006147:Guanine; D004247:DNA; D004265:DNA Helicases
DNA Helicase; DNA Repair; DNA Replication; Fanconi Anemia; G-quadruplex; Genetic Diseases; Genomic Instability