NEIL3-mediated proteasomal degradation facilitates the repair of cisplatin-induced DNA damage in human cells
Aliyaskarova U. Baiken Y. Renaud F. Couve S. Kisselev A.F. Saparbaev M. Groisman R.
December 2023Nature Research
Scientific Reports
2023#13Issue 1
Anti-neoplastic effect of DNA cross-linking agents such as cisplatin, mitomycin C, and psoralen is attributed to their ability to induce DNA interstrand cross-links (ICLs), which block replication, transcription, and linear repair pathways by preventing DNA strand separation and trigger apoptosis. It is generally agreed that the Fanconi anemia (FA) pathway orchestrates the removal of ICLs by the combined actions of various DNA repair pathways. Recently, attention has been focused on the ability of the NEIL3-initiated base excision repair pathway to resolve psoralen- and abasic site-induced ICLs in an FA-independent manner. Intriguingly, overexpression of NEIL3 is associated with chemo-resistance and poor prognosis in many solid tumors. Here, using loss- and gain-of-function approaches, we demonstrate that NEIL3 confers resistance to cisplatin and participates in the removal of cisplatin–DNA adducts. Proteomic studies reveal that the NEIL3 protein interacts with the 26S proteasome in a cisplatin-dependent manner. NEIL3 mediates proteasomal degradation of WRNIP1, a protein involved in the early step of ICL repair. We propose that NEIL3 participates in the repair of ICL-stalled replication fork by recruitment of the proteasome to ensure a timely transition from lesion recognition to repair via the degradation of early-step vanguard proteins.
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Team «Mechanisms of DNA Repair and Carcinogenesis», CNRS UMR 9019, Université Paris-Saclay, Gustave Roussy Cancer Campus, Villejuif Cedex, 94805, France
National Laboratory Astana, Nazarbayev University, Astana, Kazakhstan
School of Sciences and Humanities, Nazarbayev University, Astana, Kazakhstan
School of Engineering and Digital Sciences, Nazarbayev University, Astana, Kazakhstan
EPHE, PSL University, Paris, France
Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, PRB, 720 S. Donahue Dr., Auburn, 36849, AL, United States
Team «Mechanisms of DNA Repair and Carcinogenesis»
National Laboratory Astana
School of Sciences and Humanities
School of Engineering and Digital Sciences
EPHE
Department of Drug Discovery and Development
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