FANCJ helicase defective in Fanconia anemia and breast cancer unwinds G-quadruplex DNA to defend genomic stability.
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.
Wu
Yuliang
Y
Laboratory of Molecular Gerontology, National Institute on Aging, NIH, 5600 Nathan Shock Drive, Baltimore, Maryland 21224, USA.
Shin-ya
Kazuo
K
Brosh
Robert M
RM
D000818:Animals; D017209:Apoptosis; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism / Q000502:physiology*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D017173:Caenorhabditis elegans; D005199:Fanconi Anemia / Q000235:genetics*; D051856:Fanconi Anemia Complementation Group Proteins / Q000378:metabolism / Q000502:physiology*; D005347:Fibroblasts / Q000378:metabolism; D042822:Genomic Instability; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D009690:Nucleic Acid Conformation; D009691:Nucleic Acid Denaturation; D051716:Replication Protein A / Q000378:metabolism
C102108:BACH1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D051856:Fanconi Anemia Complementation Group Proteins; D051716:Replication Protein A