Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function

Maurice Michel; Carlos Benítez-Buelga; Patricia A. Calvo; Bishoy M.F. Hanna; Oliver Mortusewicz; Geoffrey Masuyer; Jonathan Davies; Olov Wallner; Kumar Sanjiv; Julian J. Albers; Sergio Castañeda-Zegarra; Ann Sofie Jemth; Torkild Visnes; Ana Sastre-Perona; Akhilesh N. Danda; Evert J. Homan; Karthick Marimuthu; Zhao Zhenjun; Celestine N. Chi; Antonio Sarno; Elisée Wiita; Catharina von Nicolai; Anna J. Komor; Varshni Rajagopal; Sarah Müller; Emily C. Hank; Marek Varga; Emma R. Scaletti; Monica Pandey; Stella Karsten; Hanne Haslene-Hox; Simon Loevenich; Petra Marttila; Azita Rasti; Kirill Mamonov; Florian Ortis; Fritz Schömberg; Olga Loseva; Josephine Stewart; Nicholas D'Arcy-Evans; Tobias Koolmeister; Martin Henriksson; Dana Michel; Ana de Ory; Lucia Acero; Oriol Calvete; Martin Scobie; Christian Hertweck; Ivan Vilotijevic; Christina Kalderén; Ana Osorio; Rosario Perona; Alexandra Stolz; Pål Stenmark; Ulrika Warpman Berglund; Miguel de Vega; Thomas Helleday

doi:10.1126/science.abf8980

Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function

Maurice Michel^*, Carlos Benítez-Buelga, Patricia A. Calvo, Bishoy M.F. Hanna, Oliver Mortusewicz, Geoffrey Masuyer, Jonathan Davies, Olov Wallner, Kumar Sanjiv, Julian J. Albers, Sergio Castañeda-Zegarra, Ann Sofie Jemth, Torkild Visnes, Ana Sastre-Perona, Akhilesh N. Danda, Evert J. Homan, Karthick Marimuthu, Zhao Zhenjun, Celestine N. Chi, Antonio SarnoElisée Wiita, Catharina von Nicolai, Anna J. Komor, Varshni Rajagopal, Sarah Müller, Emily C. Hank, Marek Varga, Emma R. Scaletti, Monica Pandey, Stella Karsten, Hanne Haslene-Hox, Simon Loevenich, Petra Marttila, Azita Rasti, Kirill Mamonov, Florian Ortis, Fritz Schömberg, Olga Loseva, Josephine Stewart, Nicholas D'Arcy-Evans, Tobias Koolmeister, Martin Henriksson, Dana Michel, Ana de Ory, Lucia Acero, Oriol Calvete, Martin Scobie, Christian Hertweck, Ivan Vilotijevic, Christina Kalderén, Ana Osorio, Rosario Perona, Alexandra Stolz, Pål Stenmark, Ulrika Warpman Berglund, Miguel de Vega, Thomas Helleday^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Research › peer-review

32 Citations (Scopus)

Abstract

Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease 1 (APE1) and initiating repair. Here, we describe a small molecule (TH10785) that interacts with the phenylalanine-319 and glycine-42 amino acids of OGG1, increases the enzyme activity 10-fold, and generates a previously undescribed b,d-lyase enzymatic function. TH10785 controls the catalytic activity mediated by a nitrogen base within its molecular structure. In cells, TH10785 increases OGG1 recruitment to and repair of oxidative DNA damage. This alters the repair process, which no longer requires APE1 but instead is dependent on polynucleotide kinase phosphatase (PNKP1) activity. The increased repair of oxidative DNA lesions with a small molecule may have therapeutic applications in various diseases and aging.

Original language	English
Pages (from-to)	1471-1476
Number of pages	6
Journal	Science
Volume	376
Issue number	6600
DOIs	https://doi.org/10.1126/science.abf8980
Publication status	Published - 24 Jun 2022
Externally published	Yes

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Michel, M., Benítez-Buelga, C., Calvo, P. A., Hanna, B. M. F., Mortusewicz, O., Masuyer, G., Davies, J., Wallner, O., Sanjiv, K., Albers, J. J., Castañeda-Zegarra, S., Jemth, A. S., Visnes, T., Sastre-Perona, A., Danda, A. N., Homan, E. J., Marimuthu, K., Zhenjun, Z., Chi, C. N., ... Helleday, T. (2022). Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function. Science, 376(6600), 1471-1476. https://doi.org/10.1126/science.abf8980

@article{222e73b89e4b42b39abd6ac3ba1bd636,

title = "Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function",

abstract = "Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease 1 (APE1) and initiating repair. Here, we describe a small molecule (TH10785) that interacts with the phenylalanine-319 and glycine-42 amino acids of OGG1, increases the enzyme activity 10-fold, and generates a previously undescribed b,d-lyase enzymatic function. TH10785 controls the catalytic activity mediated by a nitrogen base within its molecular structure. In cells, TH10785 increases OGG1 recruitment to and repair of oxidative DNA damage. This alters the repair process, which no longer requires APE1 but instead is dependent on polynucleotide kinase phosphatase (PNKP1) activity. The increased repair of oxidative DNA lesions with a small molecule may have therapeutic applications in various diseases and aging.",

author = "Maurice Michel and Carlos Ben{\'i}tez-Buelga and Calvo, {Patricia A.} and Hanna, {Bishoy M.F.} and Oliver Mortusewicz and Geoffrey Masuyer and Jonathan Davies and Olov Wallner and Kumar Sanjiv and Albers, {Julian J.} and Sergio Casta{\~n}eda-Zegarra and Jemth, {Ann Sofie} and Torkild Visnes and Ana Sastre-Perona and Danda, {Akhilesh N.} and Homan, {Evert J.} and Karthick Marimuthu and Zhao Zhenjun and Chi, {Celestine N.} and Antonio Sarno and Elis{\'e}e Wiita and {von Nicolai}, Catharina and Komor, {Anna J.} and Varshni Rajagopal and Sarah M{\"u}ller and Hank, {Emily C.} and Marek Varga and Scaletti, {Emma R.} and Monica Pandey and Stella Karsten and Hanne Haslene-Hox and Simon Loevenich and Petra Marttila and Azita Rasti and Kirill Mamonov and Florian Ortis and Fritz Sch{\"o}mberg and Olga Loseva and Josephine Stewart and Nicholas D'Arcy-Evans and Tobias Koolmeister and Martin Henriksson and Dana Michel and {de Ory}, Ana and Lucia Acero and Oriol Calvete and Martin Scobie and Christian Hertweck and Ivan Vilotijevic and Christina Kalder{\'e}n and Ana Osorio and Rosario Perona and Alexandra Stolz and P{\aa}l Stenmark and Berglund, {Ulrika Warpman} and {de Vega}, Miguel and Thomas Helleday",

note = "Publisher Copyright: {\textcopyright} 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works",

year = "2022",

month = jun,

day = "24",

doi = "10.1126/science.abf8980",

language = "English",

volume = "376",

pages = "1471--1476",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6600",

}

Michel, M, Benítez-Buelga, C, Calvo, PA, Hanna, BMF, Mortusewicz, O, Masuyer, G, Davies, J, Wallner, O, Sanjiv, K, Albers, JJ, Castañeda-Zegarra, S, Jemth, AS, Visnes, T, Sastre-Perona, A, Danda, AN, Homan, EJ, Marimuthu, K, Zhenjun, Z, Chi, CN, Sarno, A, Wiita, E, von Nicolai, C, Komor, AJ, Rajagopal, V, Müller, S, Hank, EC, Varga, M, Scaletti, ER, Pandey, M, Karsten, S, Haslene-Hox, H, Loevenich, S, Marttila, P, Rasti, A, Mamonov, K, Ortis, F, Schömberg, F, Loseva, O, Stewart, J, D'Arcy-Evans, N, Koolmeister, T, Henriksson, M, Michel, D, de Ory, A, Acero, L, Calvete, O, Scobie, M, Hertweck, C, Vilotijevic, I, Kalderén, C, Osorio, A, Perona, R, Stolz, A, Stenmark, P, Berglund, UW, de Vega, M & Helleday, T 2022, 'Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function', Science, vol. 376, no. 6600, pp. 1471-1476. https://doi.org/10.1126/science.abf8980

TY - JOUR

T1 - Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function

AU - Michel, Maurice

AU - Benítez-Buelga, Carlos

AU - Calvo, Patricia A.

AU - Hanna, Bishoy M.F.

AU - Mortusewicz, Oliver

AU - Masuyer, Geoffrey

AU - Davies, Jonathan

AU - Wallner, Olov

AU - Sanjiv, Kumar

AU - Albers, Julian J.

AU - Castañeda-Zegarra, Sergio

AU - Jemth, Ann Sofie

AU - Visnes, Torkild

AU - Sastre-Perona, Ana

AU - Danda, Akhilesh N.

AU - Homan, Evert J.

AU - Marimuthu, Karthick

AU - Zhenjun, Zhao

AU - Chi, Celestine N.

AU - Sarno, Antonio

AU - Wiita, Elisée

AU - von Nicolai, Catharina

AU - Komor, Anna J.

AU - Rajagopal, Varshni

AU - Müller, Sarah

AU - Hank, Emily C.

AU - Varga, Marek

AU - Scaletti, Emma R.

AU - Pandey, Monica

AU - Karsten, Stella

AU - Haslene-Hox, Hanne

AU - Loevenich, Simon

AU - Marttila, Petra

AU - Rasti, Azita

AU - Mamonov, Kirill

AU - Ortis, Florian

AU - Schömberg, Fritz

AU - Loseva, Olga

AU - Stewart, Josephine

AU - D'Arcy-Evans, Nicholas

AU - Koolmeister, Tobias

AU - Henriksson, Martin

AU - Michel, Dana

AU - de Ory, Ana

AU - Acero, Lucia

AU - Calvete, Oriol

AU - Scobie, Martin

AU - Hertweck, Christian

AU - Vilotijevic, Ivan

AU - Kalderén, Christina

AU - Osorio, Ana

AU - Perona, Rosario

AU - Stolz, Alexandra

AU - Stenmark, Pål

AU - Berglund, Ulrika Warpman

AU - de Vega, Miguel

AU - Helleday, Thomas

PY - 2022/6/24

Y1 - 2022/6/24

N2 - Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease 1 (APE1) and initiating repair. Here, we describe a small molecule (TH10785) that interacts with the phenylalanine-319 and glycine-42 amino acids of OGG1, increases the enzyme activity 10-fold, and generates a previously undescribed b,d-lyase enzymatic function. TH10785 controls the catalytic activity mediated by a nitrogen base within its molecular structure. In cells, TH10785 increases OGG1 recruitment to and repair of oxidative DNA damage. This alters the repair process, which no longer requires APE1 but instead is dependent on polynucleotide kinase phosphatase (PNKP1) activity. The increased repair of oxidative DNA lesions with a small molecule may have therapeutic applications in various diseases and aging.

AB - Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease 1 (APE1) and initiating repair. Here, we describe a small molecule (TH10785) that interacts with the phenylalanine-319 and glycine-42 amino acids of OGG1, increases the enzyme activity 10-fold, and generates a previously undescribed b,d-lyase enzymatic function. TH10785 controls the catalytic activity mediated by a nitrogen base within its molecular structure. In cells, TH10785 increases OGG1 recruitment to and repair of oxidative DNA damage. This alters the repair process, which no longer requires APE1 but instead is dependent on polynucleotide kinase phosphatase (PNKP1) activity. The increased repair of oxidative DNA lesions with a small molecule may have therapeutic applications in various diseases and aging.

UR - http://www.scopus.com/inward/record.url?scp=85132689112&partnerID=8YFLogxK

U2 - 10.1126/science.abf8980

DO - 10.1126/science.abf8980

M3 - Article

C2 - 35737787

AN - SCOPUS:85132689112

SN - 0036-8075

VL - 376

SP - 1471

EP - 1476

JO - Science

JF - Science

IS - 6600

ER -

Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function

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