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

Abstract

Background:The Fe-S helicase FANCJ implicated in Fanconi anemia plays important roles in DNA replication and repair. Results: FANCJ, but not the Fe-S XPD or DDX11 helicases, unwinds unimolecular G4 DNA. Conclusion: FANCJ is a specialized Fe-S helicase, preventing G4-induced DNA damage. Significance: FANCJ has a unique role in DNA metabolism to prevent G4 accumulation that causes genomic instability.

Mycobacterium tuberculosis DinG Is a Structure-specific Helicase That Unwinds G4 DNA

“…coli RecQ and its orthologs unwind G4 DNA structures (10 -12), and a recent study shows that EcDinG also resolves intermolecular G4 structures (22). Our study clearly demonstrates that MtDinG unwinds intermolecular G4 structures robustly even at 50 nM concentrations, indicating that MtDinG could be a functional ortholog of E. coli RecQ at least in part with G4 DNA unwinding activity.…”

“…tuberculosis DinG Unwinds G-quadruplex (G4) DNAGerm line mutations in FANCJ cause Fanconi anemia, a rare chromosome instability and cancer susceptibility genetic disorder (49 -52). Biochemical studies show that FANCJ and E. coli DinG helicases resolve G4 DNA (22,24). MtDinG is an ortholog of human FANCJ; however, it is unknown whether MtDinG can unwind G4 DNA structures.…”

“…E. coli DinG unwinds 5Ј flap structures, D-loops, and R-loops but lacks three-way and Holliday junction (HJ) unwinding activity (21). A recent study shows that E. coli DinG resolves intermolecular G4 DNA structures (22). Nonetheless, the precise role of DinG helicase in DNA repair, recombination, and replication or G4 DNA metabolism is unclear.…”

DNA Sequences Proximal to Human Mitochondrial DNA Deletion Breakpoints Prevalent in Human Disease Form G-quadruplexes, a Class of DNA Structures Inefficiently Unwound by the Mitochondrial Replicative Twinkle Helicase

“…We next assessed the ability of Twinkle helicase to unwind an entropically favored unimolecular G4 DNA substrate (poly(A) Zic1) that was shown previously to be unwound by FANCJ helicase (46). Twinkle was tested on a series of poly(A) Zic1-unimolecular G4 DNA substrates with increasing 5Ј singlestranded DNA tail lengths of 20, 30, and 40 nt and was found to be completely inactive for unwinding (Fig.…”

Novel Function of the Fanconi Anemia Group J or RECQ1 Helicase to Disrupt Protein-DNA Complexes in a Replication Protein A-stimulated Manner

“…Although FANCJ is implicated in downstream events of double strand break repair of interstrand cross-link-induced DNA damage, growing evidence suggests that FANCJ and other FA-linked gene products have roles outside the classical FA pathway. For example, FANCJ resolves G-quadruplex (G4) DNA structures to preserve chromosomal stability (10,11) and may have a unique role to suppress G4 accumulation or G4-induced DNA damage in vivo (12,13). G4 DNA (14) and three-stranded T-loops (15) are believed to be prominent structures at telomeres, and recent evidence suggests that FANCJ is found at telomeres in telomerase-negative human cells that preserve their chromosome ends by the alternative lengthening of telomeres (ALT) pathway (16).…”