More complexity to the Bloom's syndrome complex

Abstract

Bloom's syndrome is caused by mutations in the BLM gene. The BLM gene product, BLM helicase, forms a complex with two other proteins, DNA topoisomerase IIIalpha and RMI1. In this issue of Genes & Development, Wang and colleagues (2843-2855) and Meetei and colleagues (2856-2868) report the discovery of a fourth component of this complex called RMI2. RMI2 may be a representative of a new family of OB-fold-containing proteins that are important for complex stabilization and checkpoint response.

Figure 1.

Schematic diagram indicating the BLM core complex and a variety of possible subcomplexes that are thought to exist in human cells. Direct interactions between two proteins are indicated by solid black double arrows, whereas potential interactions are shown with dashed red double arrows.

Figure 2.

Potential roles of BLM and its interaction partners in human cells Schematic diagram indicating alternative pathways for the repair of stalled replication forks that arise as a result of DNA damage. Leading and lagging strand synthesis is shown in green and blue, respectively. (a–c) Following fork blockage, RAD51 recombinase can promote strand exchange between paired sisters, such that the DNA synthesis can bypass the damage in the leading strand by use of the sister chromatid. (c,d) The resulting recombination intermediate may then be dissociated by BLM–TopoIIIα to give rise to a noncrossover product. (e) Alternatively, BLM could promote fork regression to produce a chicken foot structure, or HJ, with the newly synthesized strands annealed with each other. (f) The newly synthesized strand from the undamaged parental strand can then serve as a template for lesion bypass. (d) The HJ may then be dissociated back to a replication fork allowing replication to continue. (g) A further possibility is that the 5′-end of the newly synthesized single-strand of DNA could fold back and reanneal to its original parental strand. DNA synthesis and branch migration could also give rise to dHJs (h), which in turn can be dissociated by BLM complex back to a replication fork structure without crossover formation (d). On the other hand, in the absence of a functional BLM complex, HJs formed by either fork regression (e) or by RAD51-dependent strand exchange reactions (c) could be resolved by HJ resolvases leading to DSB formation, which in turn can be repaired by homologous recombination to restore the replication fork with crossover (i). The involvement of BLM in each pathway is indicated, as are the potential roles of BLM interacting proteins (red). In some cases, the roles of BLM-interacting proteins are unknown (gray).