MUS81 cleaves TOP1‑derived lesions and other DNA-protein cross‑links

MARINI PALOMEQUE, María Victoria, Fedor NIKULENKOV, Pounami SAMADDER, Sissel JUUL, Birgitta R. KNUDSEN and Lumír KREJČÍ. MUS81 cleaves TOP1‑derived lesions and other DNA-protein cross‑links. BMC Biology. London: BMC, 2023, vol. 21, No 1, p. 1-16. ISSN 1741-7007. Available from: https://dx.doi.org/10.1186/s12915-023-01614-1.

Basic information

• Original name: MUS81 cleaves TOP1‑derived lesions and other DNA-protein cross‑links
• Authors: MARINI PALOMEQUE, María Victoria (380 Italy, belonging to the institution), Fedor NIKULENKOV (203 Czech Republic, belonging to the institution), Pounami SAMADDER (356 India, belonging to the institution), Sissel JUUL, Birgitta R. KNUDSEN and Lumír KREJČÍ (203 Czech Republic, guarantor, belonging to the institution).
• Edition: BMC Biology, London, BMC, 2023, 1741-7007.

Other information

• Original language: English
• Type of outcome: Article in a journal
• Field of Study: 10608 Biochemistry and molecular biology
• Country of publisher: United Kingdom of Great Britain and Northern Ireland
• Confidentiality degree: is not subject to a state or trade secret
• WWW: URL
• Impact factor: Impact factor: 5.400 in 2022
• RIV identification code: RIV/00216224:14110/23:00130789
• Organization unit: Faculty of Medicine
• Doi: http://dx.doi.org/10.1186/s12915-023-01614-1
• UT WoS: 000990321800001
• Keywords in English: DNA-protein cross-links repair; MUS81; TDP1; Topoisomerase 1
• Tags: 14110513, Cross-links, DNA repair, MUS81, nuclease activity, podil, rivok
• Tags: International impact, Reviewed

Abstract

Background DNA-protein cross-links (DPCs) are one of the most deleterious DNA lesions, originating from various sources, including enzymatic activity. For instance, topoisomerases, which play a fundamental role in DNA metabolic processes such as replication and transcription, can be trapped and remain covalently bound to DNA in the presence of poisons or nearby DNA damage. Given the complexity of individual DPCs, numerous repair pathways have been described. The protein tyrosyl-DNA phosphodiesterase 1 (Tdp1) has been demonstrated to be responsible for removing topoisomerase 1 (Top1). Nevertheless, studies in budding yeast have indicated that alternative pathways involving Mus81, a structure-specific DNA endonuclease, could also remove Top1 and other DPCs. Results This study shows that MUS81 can efficiently cleave various DNA substrates modified by fluorescein, streptavidin or proteolytically processed topoisomerase. Furthermore, the inability of MUS81 to cleave substrates bearing native TOP1 suggests that TOP1 must be either dislodged or partially degraded prior to MUS81 cleavage. We demonstrated that MUS81 could cleave a model DPC in nuclear extracts and that depletion of TDP1 in MUS81-KO cells induces sensitivity to the TOP1 poison camptothecin (CPT) and affects cell proliferation. This sensitivity is only partially suppressed by TOP1 depletion, indicating that other DPCs might require the MUS81 activity for cell proliferation. Conclusions Our data indicate that MUS81 and TDP1 play independent roles in the repair of CPT-induced lesions, thus representing new therapeutic targets for cancer cell sensitisation in combination with TOP1 inhibitors.

Links

• EF16_025/0007381, research and development project: Name: Preklinická progrese nových organických sloučenin s cílenou biologickou aktivitou
• GX21-22593X, research and development project: Name: Identifikace a charakterizace proteinů zahrnutých v metabolismu G-kvadruplexů a R-smyček a jejich vztah k replikaci DNA
• 206292/E/17/Z, interní kód MU: Name: Mechanics and execution of homologous recombination - biophysics to the organism

Investor: Wellcome Trust