The Holliday Model of DNA Crossover

The widely accepted model for DNA crossover was first proposed by Robin Holliday in 1964.  It involves several steps as illustrated in the following figure.

Figure 8-D-2.  The Holliday model of DNA crossover.
(a) Two homologous DNA molecules line up (e.g., two nonsister chromatids line up during meiosis).
(b) Cuts in one strand of both DNAs.
(c) The cut strands cross and join homologous strands, forming the Holliday structure (or Holliday junction).
(d) Heteroduplex region is formed by branch migration.
(e) Resolution of the Holliday structure.  Figure 8-D-2e is a different view of the Holliday junction than Figure 8-D-2d.  DNA strands may be cut along either the vertical line or horizontal line.
(f) The vertical cut will result in crossover between f-f' and F-F' regions.  The heteroduplex region will eventually be corrected by mismatch repair.
(g) The horizontal cut does not lead to crossover after mismatch repair.  However, it could cause gene conversion.

Figure 8-D-3.  The structure of the RecA hexamer (PDB ID = 2REC).  The RecA hexamer can wrap around single-stranded DNA and direct it to form the Holliday structure.

The detailed mechanism of homologous recombination was mainly obtained from the study of E. coli.  Although bacteria do no undergo meiosis, homologous recombination could occur during or immediately after DNA replication.  It may also occur in a mating process called conjugation. 

In E. coli, the recombination is initiated by the enzyme RecBCD, consisting of three subunits: RecB, RecC and RecD.  This enzyme has both helicase and nuclease activities.  The enzyme first uses its helicase activity to unwind DNA.  When it hits the Chi site (with sequence GCTGGTGG), one of the exposed strand will be cut by its nuclease activity.  The reason why this special site is called the "Chi site" is because the Greek letter c (chi) looks like a crossover point.  The Chi site is the position of the Holliday junction and also the position of chiasma.

After DNA strands are cut by RecBCD, the strand invasion is catalyzed by RecA proteins, which can wrap around single stranded DNA and direct it to form the Holliday structure.

Finally, the branch migration is catalyzed by RuvA and RuvB.  The Holliday structure is resolved by the protein RuvC.

The original Holliday model involves two single-strand breaks.  Evidence suggests that the Holliday structure could also be initiated by other alternatives:

• Double-strand break - From Kimball's Biology Pages.
• One single-strand break - proposed by M. Meselson and C. Radding in 1975 (Proc. Natl. Acad. Sci. USA, 72:358).

Review Article:

DNA Crossing: Crystal Structures of Holliday Junctions - J. Biol. Chem., 2003.