FANCJ helicase defective in Fanconia anemia and breast cancer unwinds G-quadruplex DNA to defend genomic stability.

Abstract

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.

• Authors: Yuliang Wu, Kazuo Shin-ya, Robert M Brosh Jr
• Journal: Molecular and cellular biology (Mol Cell Biol) Vol. 28 Issue 12 Pg. 4116-28 (Jun 2008) ISSN: 1098-5549 [Electronic] United States
• PMID: 18426915 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• BACH1 protein, human
• Basic-Leucine Zipper Transcription Factors
• Fanconi Anemia Complementation Group Proteins
• Replication Protein A

Topics

• Animals
• Apoptosis
• Basic-Leucine Zipper Transcription Factors (metabolism, physiology)
• Breast Neoplasms (genetics, pathology)
• Caenorhabditis elegans
• Fanconi Anemia (genetics)
• Fanconi Anemia Complementation Group Proteins (metabolism, physiology)
• Fibroblasts (metabolism)
• Genomic Instability
• HeLa Cells
• Humans
• Mice
• Models, Biological
• Mutation
• Nucleic Acid Conformation
• Nucleic Acid Denaturation
• Replication Protein A (metabolism)