FANCJ mutations are associated with breast cancer and genetically linked to the 
bone marrow disease Fanconi anemia (FA). The genomic instability of FA-J mutant 
cells suggests that FANCJ helicase functions in the replicational stress 
response. A putative helicase with sequence similarity to FANCJ in 
Caenorhabditis elegans (DOG-1) and mouse (RTEL) is required for poly(G) tract 
maintenance, suggesting its involvement in the resolution of alternate DNA 
structures that impede replication. Under physiological conditions, guanine-rich 
sequences spontaneously assemble into four-stranded structures (G quadruplexes 
[G4]) that influence genomic stability. FANCJ unwound G4 DNA substrates in an 
ATPase-dependent manner. FANCJ G4 unwinding is specific since another 
superfamily 2 helicase, RECQ1, failed to unwind all G4 substrates tested under 
conditions in which the helicase unwound duplex DNA. Replication protein A 
stimulated FANCJ G4 unwinding, whereas the mismatch repair complex MSH2/MSH6 
inhibited this activity. FANCJ-depleted cells treated with the G4-interactive 
compound telomestatin displayed impaired proliferation and elevated levels of 
apoptosis and DNA damage compared to small interfering RNA control cells, 
suggesting that G4 DNA is a physiological substrate of FANCJ. Although the FA 
pathway has been classically described in terms of interstrand cross-link (ICL) 
repair, the cellular defects associated with FANCJ mutation extend beyond the 
reduced ability to repair ICLs and involve other types of DNA structural 
roadblocks to replication.