HELQ is required for replication-coupled DNA repair, germ-cell maintenance, and tumor suppression.
Major finding: HELQ is required for replication-coupled DNA repair, germ-cell maintenance, and tumor suppression.
Mechanism: HELQ promotes homologous recombination at replication forks via interaction with RAD51 paralogues.
Impact: HELQ acts in parallel to the Fanconi anemia pathway to control interstrand crosslink repair.
Interstrand crosslinks (ICL) prevent DNA replication fork progression and are repaired via homologous recombination by replication stress response factors including components of the Fanconi anemia pathway. Studies in Drosophila melanogaster and Caenorhabditis elegans have suggested that the DNA helicase HELQ contributes to replication fork unwinding and ICL repair, but the function of HELQ in mammalian cells is unknown. Adelman and colleagues found that Helq-deficient mice were viable but exhibited a fertility defect characterized by testicular and ovarian atrophy and decreased stem cells. In addition, Helq deficiency was associated with increased frequency of tumor incidence, in particular ovarian tumors and pituitary adenomas, as well as enhanced tumor predisposition in heterozygous mice, suggesting that HELQ may function as a haploinsufficient tumor suppressor. Similar to Fanconi anemia models, Helq loss increased the sensitivity of hematopoietic stem and progenitor cells to ICL-inducing agents and induced chromosomal aberrations, supporting a role for HELQ in ICL repair. Consistent with this idea, HELQ interacted with replication checkpoint and DNA repair proteins involved in repair at stalled replication forks, including ataxia telangiectasia and Rad3-related (ATR), Fanconi anemia proteins, and the RAD51 paralogue complex BCDX2 (which is composed of RAD51B, RAD51C, RAD51D, and XRCC2), and triggered replication fork asymmetry and decreased replication fork extension, indicative of fork stalling and collapse. Furthermore, HELQ functioned in parallel to the Fanconi anemia pathway and was required for efficient homologous recombination; loss of Helq resulted in impaired DNA repair and persistence of double-strand breaks downstream of RAD51 recruitment to repair foci. These results identify HELQ as an important mediator of replication-coupled DNA repair and suggest that this function is essential for germ cell maintenance and tumor suppression in mammals.
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