PARylation prevents the proteasomal degradation of topoisomerase I DNA-protein crosslinks and induces their deubiquitylation

Yilun Sun (), Jiji Chen, Shar-yin N. Huang, Yijun P. Su, Wenjie Wang, Keli Agama, Sourav Saha, Lisa M. Jenkins, John M. Pascal and Yves Pommier ()
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Yilun Sun: National Cancer Institute, NIH
Jiji Chen: National Institute of Biomedical Imaging and Bioengineering, NIH
Shar-yin N. Huang: National Cancer Institute, NIH
Yijun P. Su: National Institute of Biomedical Imaging and Bioengineering, NIH
Wenjie Wang: National Cancer Institute, NIH
Keli Agama: National Cancer Institute, NIH
Sourav Saha: National Cancer Institute, NIH
Lisa M. Jenkins: National Cancer Institute, NIH
John M. Pascal: Université de Montréal
Yves Pommier: National Cancer Institute, NIH

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract Poly(ADP)-ribosylation (PARylation) regulates chromatin structure and recruits DNA repair proteins. Using single-molecule fluorescence microscopy to track topoisomerase I (TOP1) in live cells, we found that sustained PARylation blocked the repair of TOP1 DNA-protein crosslinks (TOP1-DPCs) in a similar fashion as inhibition of the ubiquitin-proteasome system (UPS). PARylation of TOP1-DPC was readily revealed by inhibiting poly(ADP-ribose) glycohydrolase (PARG), indicating the otherwise transient and reversible PARylation of the DPCs. As the UPS is a key repair mechanism for TOP1-DPCs, we investigated the impact of TOP1-DPC PARylation on the proteasome and found that the proteasome is unable to associate with and digest PARylated TOP1-DPCs. In addition, PARylation recruits the deubiquitylating enzyme USP7 to reverse the ubiquitylation of PARylated TOP1-DPCs. Our work identifies PARG as repair factor for TOP1-DPCs by enabling the proteasomal digestion of TOP1-DPCs. It also suggests the potential regulatory role of PARylation for the repair of a broad range of DPCs.

Date: 2021
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DOI: 10.1038/s41467-021-25252-9

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