Mutations in FANCJ cause Fanconi anaemia, a cancer predisposition syndrome. Absence of FANCJ helicase activity causes sensitivity to replication inhibitors, but the molecular basis for this is unclear. Niedzwiedz and colleagues now demonstrate that FANCJ counteracts fork stalling in the presence of replication barriers and prevents chromatin compaction associated with perturbed replication (J. Cell Biol. 201, 33–48; 2013).

The authors find that FANCJ helicase activity is needed to facilitate replication in the presence of replication stress. Cells lacking FANCJ do not show altered stability of replication forks (unlike other Fanconi anaemia protein mutations), and the authors suggest that that the enzyme facilitates fork passage through sites that are hard to replicate. Supporting this idea, stabilization of G4 motifs, rare replication-resistant DNA structures, causes replication stalling in FANCJ-deficient cells. The absence of FANCJ causes the formation of single-strand DNA gaps, indicating that stalled replication forks skip over fork barriers on the lagging strand. Replication fork progression is coupled to chromatin maturation, and FANCJ-deficient cells are also found to contain more compact chromatin.

Replication stalling is known to stabilize the interaction of the histone chaperone Asf1 with the Mcm2-7 complex, and to locally increase the amount of newly synthesized histone H3. These features are enhanced in FANCJ-deficient cells, and the authors detect increased accumulation of H3 molecules with methylated lysines associated with heterochromatin at stalled forks, which could explain the effect on chromatin state.