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

J 2023

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

MARINI PALOMEQUE, María Victoria, Fedor NIKULENKOV, Pounami SAMADDER, Sissel JUUL, Birgitta R. KNUDSEN et. al.

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

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10608 Biochemistry and molecular biology

Country of publisher

United Kingdom of Great Britain and Northern Ireland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

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

Abstract

V originále

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

Citovat

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.

@article{2283157,
   author = {Marini Palomeque, María Victoria and Nikulenkov, Fedor and Samadder, Pounami and Juul, Sissel and Knudsen, Birgitta R. and Krejčí, Lumír},
   article_location = {London},
   article_number = {1},
   doi = {http://dx.doi.org/10.1186/s12915-023-01614-1},
   keywords = {DNA-protein cross-links repair; MUS81; TDP1; Topoisomerase 1},
   language = {eng},
   issn = {1741-7007},
   journal = {BMC Biology},
   title = {MUS81 cleaves TOP1‑derived lesions and other DNA-protein cross‑links},
   url = {https://doi.org/10.1186/s12915-023-01614-1},
   volume = {21},
   year = {2023}
}

TY  - JOUR
ID  - 2283157
AU  - Marini Palomeque, María Victoria - Nikulenkov, Fedor - Samadder, Pounami - Juul, Sissel - Knudsen, Birgitta R. - Krejčí, Lumír
PY  - 2023
TI  - MUS81 cleaves TOP1‑derived lesions and other DNA-protein cross‑links
JF  - BMC Biology
VL  - 21
IS  - 1
SP  - 1-16
EP  - 1-16
PB  - BMC
SN  - 17417007
KW  - DNA-protein cross-links repair
KW  - MUS81
KW  - TDP1
KW  - Topoisomerase 1
UR  - https://doi.org/10.1186/s12915-023-01614-1
N2  - 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.
ER  -

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. \textit{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.

Detailed Information on Publication Record