The ZGRF1 Helicase Promotes Recombinational Repair of Replication-Blocking DNA Damage in Human Cells

  • Cell Rep. 2020 Jul 7;32(1):107849. doi: 10.1016/j.celrep.2020.107849.
André Brannvoll  1 ,  Xiaoyu Xue  2 ,  Youngho Kwon  3 ,  Smaragdi Kompocholi  4 ,  Anne Katrine W Simonsen  4 ,  Keerthana S Viswalingam  4 ,  Leticia Gonzalez  2 ,  Ian D Hickson  5 ,  Vibe H Oestergaard  4 ,  Hocine W Mankouri  5 ,  Patrick Sung  3 ,  Michael Lisby  6
Affiliations
  • 1. Department of Biology, University of Copenhagen, 2200 Copenhagen N, Denmark; Center for Chromosome Stability, Department of Cellular and Molecular Medicine, University of Copenhagen, 2200 Copenhagen N, Denmark.
  • 2. Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX 78666, USA.
  • 3. Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
  • 4. Department of Biology, University of Copenhagen, 2200 Copenhagen N, Denmark.
  • 5. Center for Chromosome Stability, Department of Cellular and Molecular Medicine, University of Copenhagen, 2200 Copenhagen N, Denmark.
  • 6. Department of Biology, University of Copenhagen, 2200 Copenhagen N, Denmark; Center for Chromosome Stability, Department of Cellular and Molecular Medicine, University of Copenhagen, 2200 Copenhagen N, Denmark. Electronic address: [email protected].
PMID: 32640219 DOI: 10.1016/j.celrep.2020.107849
Abstract

Replication-blocking DNA lesions are particularly toxic to proliferating cells because they can lead to chromosome mis-segregation if not repaired prior to Mitosis. In this study, we report that ZGRF1 null cells accumulate chromosome aberrations following replication perturbation and show sensitivity to two potent replication-blocking Anticancer drugs: mitomycin C and camptothecin. Moreover, ZGRF1 null cells are defective in catalyzing DNA damage-induced sister chromatid exchange despite accumulating excessive FANCD2, RAD51, and γ-H2AX foci upon induction of interstrand DNA crosslinks. Consistent with a direct role in promoting recombinational DNA repair, we show that ZGRF1 is a 5'-to-3' helicase that catalyzes D-loop dissociation and Holliday junction branch migration. Moreover, ZGRF1 physically interacts with RAD51 and stimulates strand exchange catalyzed by RAD51-RAD54. On the basis of these data, we propose that ZGRF1 promotes repair of replication-blocking DNA lesions through stimulation of homologous recombination.

Keywords
D-loop dissociation; DNA helicase; FANCD2; FANCJ; FANCM; Fanconi anemia; RAD51; homologous recombination; interstrand DNA crosslink repair; sister-chromatid exchange.