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An Aurora B-RPA signaling axis secures chromosome segregation fidelity

Author

Listed:
  • Poonam Roshan

    (St. Louis University)

  • Sahiti Kuppa

    (St. Louis University School of Medicine)

  • Jenna R. Mattice

    (Montana State University)

  • Vikas Kaushik

    (St. Louis University School of Medicine)

  • Rahul Chadda

    (St. Louis University School of Medicine)

  • Nilisha Pokhrel

    (Marquette University)

  • Brunda R. Tumala

    (St. Louis University School of Medicine)

  • Aparna Biswas

    (St. Louis University)

  • Brian Bothner

    (Montana State University)

  • Edwin Antony

    (St. Louis University School of Medicine)

  • Sofia Origanti

    (St. Louis University)

Abstract

Errors in chromosome segregation underlie genomic instability associated with cancers. Resolution of replication and recombination intermediates and protection of vulnerable single-stranded DNA (ssDNA) intermediates during mitotic progression requires the ssDNA binding protein Replication Protein A (RPA). However, the mechanisms that regulate RPA specifically during unperturbed mitotic progression are poorly resolved. RPA is a heterotrimer composed of RPA70, RPA32 and RPA14 subunits and is predominantly regulated through hyperphosphorylation of RPA32 in response to DNA damage. Here, we have uncovered a mitosis-specific regulation of RPA by Aurora B kinase. Aurora B phosphorylates Ser-384 in the DNA binding domain B of the large RPA70 subunit and highlights a mode of regulation distinct from RPA32. Disruption of Ser-384 phosphorylation in RPA70 leads to defects in chromosome segregation with loss of viability and a feedback modulation of Aurora B activity. Phosphorylation at Ser-384 remodels the protein interaction domains of RPA. Furthermore, phosphorylation impairs RPA binding to DSS1 that likely suppresses homologous recombination during mitosis by preventing recruitment of DSS1-BRCA2 to exposed ssDNA. We showcase a critical Aurora B-RPA signaling axis in mitosis that is essential for maintaining genomic integrity.

Suggested Citation

  • Poonam Roshan & Sahiti Kuppa & Jenna R. Mattice & Vikas Kaushik & Rahul Chadda & Nilisha Pokhrel & Brunda R. Tumala & Aparna Biswas & Brian Bothner & Edwin Antony & Sofia Origanti, 2023. "An Aurora B-RPA signaling axis secures chromosome segregation fidelity," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38711-2
    DOI: 10.1038/s41467-023-38711-2
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