2. Academic Validation
  3. The ZGRF1 Helicase Promotes Recombinational Repair of Replication-Blocking DNA Damage in Human Cells

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

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: mlisby@bio.ku.dk.
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.

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