Lagging strand gap suppression connects BRCA-mediated fork protection to nucleosome assembly through PCNA-dependent CAF-1 recycling

Tanay Thakar, Ashna Dhoonmoon, Joshua Straka, Emily M. Schleicher, Claudia M. Nicolae and George-Lucian Moldovan ()
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Tanay Thakar: The Pennsylvania State University College of Medicine
Ashna Dhoonmoon: The Pennsylvania State University College of Medicine
Joshua Straka: The Pennsylvania State University College of Medicine
Emily M. Schleicher: The Pennsylvania State University College of Medicine
Claudia M. Nicolae: The Pennsylvania State University College of Medicine
George-Lucian Moldovan: The Pennsylvania State University College of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract The inability to protect stalled replication forks from nucleolytic degradation drives genome instability and underlies chemosensitivity in BRCA-deficient tumors. An emerging hallmark of BRCA-deficiency is the inability to suppress replication-associated single-stranded DNA (ssDNA) gaps. Here, we report that lagging strand ssDNA gaps interfere with the ASF1-CAF-1 nucleosome assembly pathway, and drive fork degradation in BRCA-deficient cells. We show that CAF-1 function at replication forks is lost in BRCA-deficient cells, due to defects in its recycling during replication stress. This CAF-1 recycling defect is caused by lagging strand gaps which preclude PCNA unloading, causing sequestration of PCNA-CAF-1 complexes on chromatin. Importantly, correcting PCNA unloading defects in BRCA-deficient cells restores CAF-1-dependent fork stability. We further show that the activation of a HIRA-dependent compensatory histone deposition pathway restores fork stability to BRCA-deficient cells. We thus define lagging strand gap suppression and nucleosome assembly as critical enablers of BRCA-mediated fork stability.

Date: 2022
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DOI: 10.1038/s41467-022-33028-y

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