Bloom syndrome (BS) is a cancer-predisposition disorder that is caused by mutations in the BLM gene, which encodes a DNA helicase of the RecQ family. BLM forms a core protein complex, together with topoisomerase-3α (TOP3α) and the recently identified RMI1 (RecQ-mediated genome instability protein-1), that resolves double Holliday junctions (dHJs) — a DNA intermediate formed dur-ing homologous recombination. Resolution of dHJs is necessary to avoid chromosomal rearrangements and preserve genome stability. Two groups have now identified a fourth member of the core complex, RMI2, which is crucial for maintaining genome stability.

The groups of Wang and Meetei purified an 18–20-kDa polypeptide, which they named RMI2. The protein co-immunoprecipitated with components of the core complex and, reciprocally, an RMI2 antibody precipitated the core components. Together, this suggests that RMI2

is part of the BLM core complex. RMI2 contains a putative oligonu-cleotide-binding (OB)-fold domain, which mediates protein–protein interactions but differs from other OB-fold complexes in that it lacks nucleic acid-binding activity. An OB-fold domain in the C terminus of RMI1 was identified as the bind-ing site for RMI2, and expression and purification of recombinant RMI1 and RMI2 revealed a stable heterodimeric complex.

But what is the functional role of the RMI1–RMI2 subcomplex within the BLM core complex? Both groups reported a decrease in the levels of TOP3α and RMI1 following deple-tion of RMI2; Wang and colleagues found that BLM levels were only weakly reduced, whereas Meetei and colleagues did not observe a dependence of BLM on RMI2. So, RMI2 is required for the stability of some, if not all, of the components of the core complex.

The hallmark of BS cells is an elevated level of sister chromatid

exchange (SCE), which is due to the inability of the core BLM complex to resolve dHJs. RMI2–/– cells were shown to have elevated SCE levels and increased chromosomal abnor-malities. The Meetei team showed that the presence of the RMI1–RMI2 subcomplex, in addition to BLM and TOP3α, stimulates the resolution of dHJs in vitro. The Wang team fur-ther demonstrated that a point muta-tion in the OB-fold domain of RMI2 disrupts the interaction between BLM and the rest of the complex (although it stabilizes TOP3α and RMI1) and abrogates the ability to suppress elevated SCE. This suggests that the interaction between RMI1 and RMI2 is crucial for dHJ resolu-tion and, therefore, genome stability.

Arianne Heinrichs

ORIGINAL RESEARCH PAPERS Xu, D. et al. RMI, a new OB-fold complex essential for Bloom syndrome protein to maintain genome stability. Genes Dev. 22, 2843–2855 (2008) | Singh, T. R. et al. BLAP18/RMI2, a novel OB-fold-containing protein, is an essential component of the Bloom helicase–double Holliday junction dissolvasome. Genes Dev. 22, 2856–2868 (2008)

m E C H A N I S m S O f d I S E A S E

Supporting stability

…the interaction between RMI1 and RMI2 is crucial for dHJ resolution…

R e s e a R c h h i g h l i g h t s

NATuRE REvIEWS | molecular cell biology vOLuME 9 | DECEMBER 2008

Nature Reviews Molecular Cell Biology | AOP, published online 30 October 2008; doi:10.1038/nrm2544