FBH1: A new checkpoint factor

Unraveling the machineries that deal with threats during DNA replication is of critical importance to understand how cells maintain genome stability. Faithful duplication of the genome is fundamental for the propagation of life, yet DNA is particularly vulnerable during the replication process. DNA replication forks encounter a large number of obstacles in the template DNA in each cell cycle. These perturbations lead to fork stalling and if not quickly resolved the fork can collapse through disassembly of the replication machinery. In case of widespread stalling of forks cells enter a state commonly referred to as 'replicative stress' that challenge genome stability. Cellular mechanisms have evolved to monitor this process and ensure completion of genome replication by different means. Following replication stress, cell cycle checkpoint pathways are activated to stabilize stalled replication forks and halt cell cycle progression. Genome duplication is then completed by employing several pathways, which include the activation of nearby dormant replication origins, the repriming of DNA replication downstream of the damage site, and tolerance to the damage thanks to lesion bypass mediated by specialized DNA polymerases [1]. The mechanisms underlying critical processes at the DNA replication fork still remain to be fully elucidated, and new important factors are emerging. The FBH1 helicase is a less investigated regulator of the response to stalled replication forks. FBH1 is a member of the conserved UvrD family of 3'-5' DNA helicases [2] that has been shown to operate on a number of cellular substrates including stalled replication forks. FBH1 accumulates at stalled forks shortly after exposure to hydroxurea (HU), a chemotherapeutic agent inducing replication stress by depleting the pool of dNTPs required for DNA synthesis. In our laboratory, we have recently identified FBH1 as the first enzyme responsible for fork regression in vivo in higher eukaryotes [3], an activity observed following hydroxyurea-induced stalling of forks. Replication fork regression is the process where a replication fork is converted to a four-way DNA junction. This is achieved by coordinated annealing of the two newly synthesized strands at the fork, the leading and the lagging strands of DNA replication. This new annealed DNA double-strand form the fourth arm of the four-way DNA junction [4]. Importantly, FBH1 also possesses fork regression activity in vitro supporting that FBH1 is a bona fide fork regression enzyme in mammalian cells [3]. What is the role of FBH1-mediated replication fork regression? This process can either be an end product …