FANCM: fork pause, rewind and play

Abstract

DNA lesions or genomic regions that are difficult to traverse frequently hinder or block DNA replication. In response to replication fork stalling, the cell activates the replication stress response pathway, which acts to protect the fork from collapse, promotes the repair or bypass of the blockage and facilitates the resumption of DNA synthesis. In this issue of the EMBO Journal, two studies conducted by the Constantinou and Niedzwiedz laboratories shed light on how the DNA translocase FANCM acts to regulate the replication stress response (Luke-Glaser et al, 2009; Schwab et al, 2009). These studies help to explain how FANCM (mutated in the human cancer predisposition syndrome, Fanconi's anaemia (FA)) co-ordinately regulates checkpoint signalling and replication fork progression.

Figure 1

(A) Replication forks can be stalled by secondary structures or DNA lesions (star) that must be removed or by-passed for replication to proceed. The DNA translocase activity of FANCM remodels the stalled fork to facilitate activation of the ATR–ATRIP kinase complex. FANCM also interacts with HCLK2 and TopBP1 to further facilitate efficient ATR activation. FANCM may also act with the BLM helicase to facilitate replication restart. (B) Stalled forks are unstable in the absence of FANCM and accumulate extensive regions of ssDNA-RPA (red circles). Although the ATR–ATRIP complex is recruited to these sites, the checkpoint is not efficiently activated because of a failure to retain TopBP1 on chromatin and/or loss of Chk1.