A Double Holliday Junction Dissolvasome Comprising BLM, Topoisomerase IIIα, and BLAP75

Abstract

Bloom syndrome (BS), an autosomal recessive disorder, is marked by a high incidence of cancer early in life. Cells derived from BS patients are unstable genetically and exhibit frequent sister chromatid exchanges, reflective of homologous recombination (HR) deregulation. BLM, the RecQ-like helicase mutated in BS, is found in several cellular protein complexes, all of which contain topoisomerase IIIalpha (Topo IIIalpha) and a novel protein BLAP75. Here, using highly purified human proteins, we show that BLAP75 associates independently with both Topo IIIalpha and BLM. Even though BLM and Topo IIIalpha can dissolve the double Holliday junction (DHJ) to yield non-crossover recombinants (1), under physiological conditions, DHJ dissolution becomes completely dependent on BLAP75. The effect of BLAP75 on BLM-Topo IIIalpha is highly specific, as it is not seen with the combination of Topo IIIalpha and Escherichia coli RecQ helicase or another human RecQ-like helicase WRN. Thus, BLM, Topo IIIalpha, and BLAP75 constitute a dissolvasome complex that processes HR intermediates to limit DNA crossover formation. This function of the BLM-Topo IIIalpha-BLAP75 dissolvasome is likely indispensable for genome maintenance and cancer avoidance.