HELQ promotes RAD51 paralog-dependent repair to avert germ cell attrition and tumourigenesis

Abstract

Repair of interstrand crosslinks (ICLs) requires the coordinate action of the intra-S phase checkpoint and the Fanconi Anemia (FA) pathway, which promote ICL incision, translesion synthesis, and homologous recombination (reviewed in ^{1, 2} ). Previous studies have implicated the 3′-5′ superfamily 2 helicase HELQ/Hel308 in ICL repair in D. melanogaster (known as Mus301 or Spn-C ³ ) and C. elegans (known as Helq-1 or Hel-308 ⁴ ). While in vitro analysis suggests that HELQ preferentially unwinds synthetic replication fork substrates with 3′ ssDNA overhangs and also disrupts protein/DNA interactions while translocating along DNA ^{5, 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 paralog complex, BCDX2, and functions in parallel to the FA pathway to promote efficient HR 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.