The Bloom syndrome complex senses RPA-coated single-stranded DNA to restart stalled replication forks

Ann-Marie K. Shorrocks, Samuel E. Jones, Kaima Tsukada, Carl A. Morrow, Zoulikha Belblidia, Johanna Shen, Iolanda Vendrell, Roman Fischer, Benedikt M. Kessler and Andrew N. Blackford ()
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Ann-Marie K. Shorrocks: University of Oxford, John Radcliffe Hospital
Samuel E. Jones: University of Oxford, John Radcliffe Hospital
Kaima Tsukada: University of Oxford, John Radcliffe Hospital
Carl A. Morrow: University of Oxford, John Radcliffe Hospital
Zoulikha Belblidia: University of Oxford, John Radcliffe Hospital
Johanna Shen: University of Oxford, John Radcliffe Hospital
Iolanda Vendrell: Department of Oncology, University of Oxford
Roman Fischer: University of Oxford
Benedikt M. Kessler: University of Oxford
Andrew N. Blackford: University of Oxford, John Radcliffe Hospital

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract The Bloom syndrome helicase BLM interacts with topoisomerase IIIα (TOP3A), RMI1 and RMI2 to form the BTR complex, which dissolves double Holliday junctions to produce non-crossover homologous recombination (HR) products. BLM also promotes DNA-end resection, restart of stalled replication forks, and processing of ultra-fine DNA bridges in mitosis. How these activities of the BTR complex are regulated in cells is still unclear. Here, we identify multiple conserved motifs within the BTR complex that interact cooperatively with the single-stranded DNA (ssDNA)-binding protein RPA. Furthermore, we demonstrate that RPA-binding is required for stable BLM recruitment to sites of DNA replication stress and for fork restart, but not for its roles in HR or mitosis. Our findings suggest a model in which the BTR complex contains the intrinsic ability to sense levels of RPA-ssDNA at replication forks, which controls BLM recruitment and activation in response to replication stress.

Date: 2021
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DOI: 10.1038/s41467-020-20818-5

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