Molecular Biology

Fragile DNA

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Science  13 Jun 2008:
Vol. 320, Issue 5882, pp. 1397
DOI: 10.1126/science.320.5882.1397a

The iconic image of DNA is a double helix, yet it can also adopt more exotic conformations such as the guanine (G) quadruplex, where four strands of G-rich DNA align (intra- or intermolecularly) in a stacked rectangular arrangement via Hoogsteen bonds between the Gs. Although the in vitro evidence for such structures is plentiful, the extent (or, indeed, the consequence) of their existence in vivo is less clear. It is known that runs of Gs are vulnerable to deletion and that a protein linked to Fanconi anemia, FancJ, can help to protect such fragile sites.

In Caenorhabditis in which the FancJ homolog dog-1 is deleted, Kruisselbrink et al. show that the G4 DNA tracts most prone to deletion have the characteristics of a canonical G quadruplex and that G3 sites—those missing one of the four legs—are not fragile. Furthermore, within the G-rich sequences, those with the greatest ability to fold into a quadruplex are most likely to suffer deletion, occasionally at a very high frequency. The small size of the deletions, less than 300 base pairs, suggests that G4 DNA preferentially stalls the replication machinery on the lagging strand, the tangled mess being extricated only by removal of the offending region up to the nearest upstream Okazaki fragment. The loss of FancJ in Fanconi anemia patients may sensitize over 300,000 predicted G4 sites in the genome to deletion, and thence produce a predisposition to cancer. — GR

Curr. Biol. 18, 10.1016/j.cub.2008.05.013 (2008).

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