FANCJ promotes PARP1 activity during DNA replication that is essential in BRCA1 deficient cells

Ke Cong, Nathan MacGilvary, Silviana Lee, Shannon G. MacLeod, Jennifer Calvo, Min Peng, Arne Nedergaard Kousholt, Tovah A. Day and Sharon B. Cantor ()
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Ke Cong: University of Massachusetts Chan Medical School
Nathan MacGilvary: University of Massachusetts Chan Medical School
Silviana Lee: University of Massachusetts Chan Medical School
Shannon G. MacLeod: Northeastern University Biology Department 360 Huntington Avenue
Jennifer Calvo: University of Massachusetts Chan Medical School
Min Peng: University of Massachusetts Chan Medical School
Arne Nedergaard Kousholt: Oncode Institute, The Netherlands Cancer Institute
Tovah A. Day: Northeastern University Biology Department 360 Huntington Avenue
Sharon B. Cantor: University of Massachusetts Chan Medical School

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract The effectiveness of poly (ADP-ribose) polymerase inhibitors (PARPi) in creating single-stranded DNA gaps and inducing sensitivity requires the FANCJ DNA helicase. Yet, how FANCJ relates to PARP1 inhibition or trapping, which contribute to PARPi toxicity, remains unclear. Here, we find PARPi effectiveness hinges on S-phase PARP1 activity, which is reduced in FANCJ deficient cells as G-quadruplexes sequester PARP1 and MSH2. Additionally, loss of the FANCJ-MLH1 interaction diminishes PARP1 activity; however, depleting MSH2 reinstates PARPi sensitivity and gaps. Indicating sequestered and trapped PARP1 are distinct, FANCJ loss increases PARPi resistance in cells susceptible to PARP1 trapping. However, with BRCA1 deficiency, the loss of FANCJ mirrors PARP1 loss or inhibition, with the detrimental commonality being loss of S-phase PARP1 activity. These insights underline the crucial role of PARP1 activity during DNA replication in BRCA1 deficient cells and emphasize the importance of understanding drug mechanisms for enhancing therapeutic response.

Date: 2024
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DOI: 10.1038/s41467-024-46824-5

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