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Molecular and Cellular Biology, June 2008, p. 4116-4128, Vol. 28, No. 12
0270-7306/08/$08.00+0     doi:10.1128/MCB.02210-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

FANCJ Helicase Defective in Fanconia Anemia and Breast Cancer Unwinds G-Quadruplex DNA To Defend Genomic Stability{triangledown} ,{dagger}

Yuliang Wu,1 Kazuo Shin-ya,2 and Robert M. Brosh Jr.1*

Laboratory of Molecular Gerontology, National Institute on Aging, NIH, 5600 Nathan Shock Drive, Baltimore, Maryland 21224,1 National Institute of Advanced Industrial Science and Technology, Tokyo 135-0064, Japan2

Received 13 December 2007/ Returned for modification 11 February 2008/ Accepted 7 April 2008

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.

* Corresponding author. Mailing address: Laboratory of Molecular Gerontology, NIA, NIH, 5600 Nathan Shock Dr., Baltimore, MD 21224. Phone: (410) 558-8578. Fax: (410) 558-8157. E-mail: BroshR{at}grc.nia.nih.gov

{triangledown} Published ahead of print on 21 April 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, June 2008, p. 4116-4128, Vol. 28, No. 12
0270-7306/08/$08.00+0     doi:10.1128/MCB.02210-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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