NDLI: Specialization among Iron-Sulfur Cluster Helicases to Resolve G-quadruplex DNA Structures That Threaten Genomic Stability

Content Provider	Journal of Biological Chemistry (JBC)
Author	Bharti, Sanjay Kumar Sommers, Joshua A. George, Fourbears Kuper, Jochen Hamon, Florian Shin-ya, Kazuo Teulade-Fichou, Marie-Paule Kisker, Caroline Jr, Robert M. Brosh Brosh, Robert M.
Abstract	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.
Related Links	http://www.jbc.org/content/288/39/28217.abstract
Ending Page	28229
Starting Page	28217
Page Count	13
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	39
Volume Number	288
DOI	10.1074/jbc.M113.496463
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2013-09-27
Access Restriction	Open
Subject Keyword	DNA Helicase DNA Repair DNA Replication Genetic Diseases Genomic Instability Fanconi Anemia G-quadruplex Molecular Bases of Disease
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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