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Simon Boulton : HELQ functions in maintaining genome stability

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Previous studies have implicated the 3'-5' superfamily 2 helicase HELQ/Hel308 in ICL repair in D. melanogaster (known as Mus301 or Spn-C) and C. elegans (known as Helq-1 or Hel-308). 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, little was known regarding its functions in mammalian organisms.

Detection and faithful repair of damaged DNA is essential for genome integrity. 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. Previous studies have implicated the 3'-5' superfamily 2 helicase HELQ/Hel308 in ICL repair in D. melanogaster (known as Mus301 or Spn-C) and C. elegans (known as Helq-1 or Hel-308). 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, little was known regarding its functions in mammalian organisms.

In recent work, we established that HELQ 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 discovered that HELQ interacts directly with the RAD51 paralog BCDX2 complex and functions in parallel to the FA pathway to promote efficient HR at damaged replication forks. These results uncovered a critical role for HELQ in replication coupled DNA repair, germ cell maintenance and tumour suppression in mammals (Adelman et al., 2013; Nature. 502(7471): 381-4).

Our findings may help to explain the prevalence of non-synonymous variants in HELQ, which are significantly associated with upper aerodigestive tract cancers, particularly among smokers; and variants in HELQ associated with early menopause, which may reflect the germ cell defects and ovarian dysgenesis observed in HELQ deficient mice.

We are currently exploring the molecular basis by which HELQ and the BCDX2 complex interact and the importance of this interaction in maintaining genome stability in cells.