HELQ promotes RAD51 paralogue-dependent repair to avert germ cell loss and tumorigenesis

Abstract

Interstrand crosslink (ICL) repair involves proteins whose mutation results in the disorder Fanconi anaemia: here gene knockdown studies in mice show that the absence of HELQ, a protein previously implicated in ICL repair, compromises germ cell development and results in tumour predisposition due to defective recombination at damaged replication forks. The poorly characterized 3′–5′ superfamily 2 helicase HELQ has been implicated in the repair of interstrand crosslinks (ICLs), a type of DNA damage that is principally repaired by proteins whose mutation causes Fanconi anaemia. Simon Boulton and colleagues report the generation of a HELQ-deficient mouse. They find that the absence of the helicase compromises germ cell development and results in tumour predisposition. At the molecular level, HELQ interacts with BCDX2, a complex involved in homologous repair, and thereby facilitates recombination at damaged replication forks. Collectively, these findings point to a critical role for HELQ in replication-coupled DNA repair, germ cell maintenance and tumour avoidance. Repair of interstrand crosslinks (ICLs) requires the coordinated action of the intra-S-phase checkpoint and the Fanconi anaemia pathway, which promote ICL incision, translesion synthesis and homologous recombination (reviewed in refs 1, 2). Previous studies have implicated the 3′–5′ superfamily 2 helicase HELQ in ICL repair in Drosophila melanogaster (MUS301 (ref. 3)) and Caenorhabditis elegans (HELQ-1 (ref. 4)). Although in vitro analysis suggests that HELQ preferentially unwinds synthetic replication fork substrates with 3′ single-stranded DNA overhangs and also disrupts protein–DNA interactions while translocating along DNA5,6, little is known regarding its functions in mammalian organisms. Here we report that HELQ helicase-deficient mice exhibit subfertility, germ cell attrition, ICL sensitivity and tumour predisposition, with Helq heterozygous mice exhibiting a similar, albeit less severe, phenotype than the null, indicative of haploinsufficiency. We establish that HELQ interacts directly with the RAD51 paralogue complex BCDX2 and functions in parallel to the Fanconi anaemia pathway to promote efficient homologous recombination at damaged replication forks. Thus, our results reveal a critical role for HELQ in replication-coupled DNA repair, germ cell maintenance and tumour suppression in mammals.