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WASp modulates RPA function on single-stranded DNA in response to replication stress and DNA damage

Author

Listed:
  • Seong-Su Han

    (PennState Health Children’s Hospital
    University of Iowa Stead Family Children’s Hospital)

  • Kuo-Kuang Wen

    (PennState Health Children’s Hospital
    University of Iowa Stead Family Children’s Hospital)

  • María L. García-Rubio

    (University of Seville-CSIC-University Pablo de Olavide)

  • Marc S. Wold

    (University of Iowa Carver College of Medicine)

  • Andrés Aguilera

    (University of Seville-CSIC-University Pablo de Olavide)

  • Wojciech Niedzwiedz

    (The Institute of Cancer Research)

  • Yatin M. Vyas

    (PennState Health Children’s Hospital
    University of Iowa Stead Family Children’s Hospital)

Abstract

Perturbation in the replication-stress response (RSR) and DNA-damage response (DDR) causes genomic instability. Genomic instability occurs in Wiskott-Aldrich syndrome (WAS), a primary immunodeficiency disorder, yet the mechanism remains largely uncharacterized. Replication protein A (RPA), a single-strand DNA (ssDNA) binding protein, has key roles in the RSR and DDR. Here we show that human WAS-protein (WASp) modulates RPA functions at perturbed replication forks (RFs). Following genotoxic insult, WASp accumulates at RFs, associates with RPA, and promotes RPA:ssDNA complexation. WASp deficiency in human lymphocytes destabilizes RPA:ssDNA-complexes, impairs accumulation of RPA, ATR, ETAA1, and TOPBP1 at genotoxin-perturbed RFs, decreases CHK1 activation, and provokes global RF dysfunction. las17 (yeast WAS-homolog)-deficient S. cerevisiae also show decreased ScRPA accumulation at perturbed RFs, impaired DNA recombination, and increased frequency of DNA double-strand break (DSB)-induced single-strand annealing (SSA). Consequently, WASp (or Las17)-deficient cells show increased frequency of DSBs upon genotoxic insult. Our study reveals an evolutionarily conserved, essential role of WASp in the DNA stress-resolution pathway, such that WASp deficiency provokes RPA dysfunction-coupled genomic instability.

Suggested Citation

  • Seong-Su Han & Kuo-Kuang Wen & María L. García-Rubio & Marc S. Wold & Andrés Aguilera & Wojciech Niedzwiedz & Yatin M. Vyas, 2022. "WASp modulates RPA function on single-stranded DNA in response to replication stress and DNA damage," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31415-z
    DOI: 10.1038/s41467-022-31415-z
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    References listed on IDEAS

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    1. Benjamin R. Schrank & Tomas Aparicio & Yinyin Li & Wakam Chang & Brian T. Chait & Gregg G. Gundersen & Max E. Gottesman & Jean Gautier, 2018. "Nuclear ARP2/3 drives DNA break clustering for homology-directed repair," Nature, Nature, vol. 559(7712), pages 61-66, July.
    2. Alexey Bochkarev & Richard A. Pfuetzner & Aled M. Edwards & Lori Frappier, 1997. "Structure of the single-stranded-DNA-binding domain of replication protein A bound to DNA," Nature, Nature, vol. 385(6612), pages 176-181, January.
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