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

Carrie A Adelman, Rafal L Lolo, Nicolai J Birkbak, Olga Murina, Kenichiro Matsuzaki, Zuzana Horejsi, Kalindi Parmar, Valérie Borel, J Mark Skehel, Gordon Stamp, Alan D'Andrea, Alessandro A Sartori, Charles Swanton, Simon J Boulton

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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 DNA, 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.

Original languageEnglish
Pages (from-to)381-4
Number of pages4
JournalNature
Volume502
Issue number7471
DOIs
Publication statusPublished - 17 Oct 2013

Keywords / Materials (for Non-textual outputs)

  • Carcinogenesis
  • DNA Damage
  • DNA Helicases
  • DNA Repair
  • DNA Replication
  • Fanconi Anemia
  • Fanconi Anemia Complementation Group D2 Protein
  • Rad51 Recombinase
  • Recombinational DNA Repair

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