Global and transcription-coupled repair of 8-oxoG is initiated by nucleotide excision repair proteins

Namrata Kumar; Arjan F. Theil; Vera Roginskaya; Yasmin Ali; Michael Calderon; Simon C. Watkins; Ryan P. Barnes; Patricia L. Opresko; Alex Pines; Hannes Lans; Wim Vermeulen; Bennett Van Houten

doi:10.1038/s41467-022-28642-9

Global and transcription-coupled repair of 8-oxoG is initiated by nucleotide excision repair proteins

Namrata Kumar, Arjan F. Theil, Vera Roginskaya, Yasmin Ali, Michael Calderon, Simon C. Watkins, Ryan P. Barnes, Patricia L. Opresko, Alex Pines, Hannes Lans, Wim Vermeulen, Bennett Van Houten^*

^*Corresponding author for this work

Molecular Genetics

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Abstract

UV-DDB, consisting of subunits DDB1 and DDB2, recognizes UV-induced photoproducts during global genome nucleotide excision repair (GG-NER). We recently demonstrated a noncanonical role of UV-DDB in stimulating base excision repair (BER) which raised several questions about the timing of UV-DDB arrival at 8-oxoguanine (8-oxoG), and the dependency of UV-DDB on the recruitment of downstream BER and NER proteins. Using two different approaches to introduce 8-oxoG in cells, we show that DDB2 is recruited to 8-oxoG immediately after damage and colocalizes with 8-oxoG glycosylase (OGG1) at sites of repair. 8-oxoG removal and OGG1 recruitment is significantly reduced in the absence of DDB2. NER proteins, XPA and XPC, also accumulate at 8-oxoG. While XPC recruitment is dependent on DDB2, XPA recruitment is DDB2-independent and transcription-coupled. Finally, DDB2 accumulation at 8-oxoG induces local chromatin unfolding. We propose that DDB2-mediated chromatin decompaction facilitates the recruitment of downstream BER proteins to 8-oxoG lesions.

Original language	English
Article number	974
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-28642-9
Publication status	Published - 21 Feb 2022

Bibliographical note

Funding Information:
We wish to thank Dr. Elise Fouquerel for the U2OS-FAP-TRF1 cell line. We thank Dr. Marcel P. Bruchez for providing the MG-2I and 660 nm light source. We thank Dr. Jacob Stuart-Ornstein, Dr. Roderick O’Sullivan, and Dr. Karen Arndt for helpful discussions. We also thank our lab members, Dr. Matt Schaich, Sripriya Raja, Dr. Wei Qian, Dr. Zhou Zhong and Brittani Schnable for careful reading of the manuscript. We are thankful to Dr. Jean Cadet for discussions regarding 8-oxoG lesion frequencies. Funding sources: This work was supported by NIH grants, R01ES019566, R01ES028686, and R35ES031638 (B.V.H.), R35ES030396 (P.L.O.), F32AG067710 (R.P.B.), the gravitation program CancerGenomiCs.nl (H.L., A.P., and W.V.) and TOP-CW grant (714.017.003) (A.P. and W.V.) from the Netherlands Organization for Scientific Research. Oncode Institute is partly financed by the Dutch Cancer Society.

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© 2022, The Author(s).

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Global and transcription-coupled repair of 8-oxoG is initiated by nucleotide excision repair proteinsFinal published version, 6.3 MBLicence: CC BY

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@article{b707a79d00d24a78ad1cd432fa16c157,

title = "Global and transcription-coupled repair of 8-oxoG is initiated by nucleotide excision repair proteins",

abstract = "UV-DDB, consisting of subunits DDB1 and DDB2, recognizes UV-induced photoproducts during global genome nucleotide excision repair (GG-NER). We recently demonstrated a noncanonical role of UV-DDB in stimulating base excision repair (BER) which raised several questions about the timing of UV-DDB arrival at 8-oxoguanine (8-oxoG), and the dependency of UV-DDB on the recruitment of downstream BER and NER proteins. Using two different approaches to introduce 8-oxoG in cells, we show that DDB2 is recruited to 8-oxoG immediately after damage and colocalizes with 8-oxoG glycosylase (OGG1) at sites of repair. 8-oxoG removal and OGG1 recruitment is significantly reduced in the absence of DDB2. NER proteins, XPA and XPC, also accumulate at 8-oxoG. While XPC recruitment is dependent on DDB2, XPA recruitment is DDB2-independent and transcription-coupled. Finally, DDB2 accumulation at 8-oxoG induces local chromatin unfolding. We propose that DDB2-mediated chromatin decompaction facilitates the recruitment of downstream BER proteins to 8-oxoG lesions.",

author = "Namrata Kumar and Theil, {Arjan F.} and Vera Roginskaya and Yasmin Ali and Michael Calderon and Watkins, {Simon C.} and Barnes, {Ryan P.} and Opresko, {Patricia L.} and Alex Pines and Hannes Lans and Wim Vermeulen and {Van Houten}, Bennett",

note = "Funding Information: We wish to thank Dr. Elise Fouquerel for the U2OS-FAP-TRF1 cell line. We thank Dr. Marcel P. Bruchez for providing the MG-2I and 660 nm light source. We thank Dr. Jacob Stuart-Ornstein, Dr. Roderick O{\textquoteright}Sullivan, and Dr. Karen Arndt for helpful discussions. We also thank our lab members, Dr. Matt Schaich, Sripriya Raja, Dr. Wei Qian, Dr. Zhou Zhong and Brittani Schnable for careful reading of the manuscript. We are thankful to Dr. Jean Cadet for discussions regarding 8-oxoG lesion frequencies. Funding sources: This work was supported by NIH grants, R01ES019566, R01ES028686, and R35ES031638 (B.V.H.), R35ES030396 (P.L.O.), F32AG067710 (R.P.B.), the gravitation program CancerGenomiCs.nl (H.L., A.P., and W.V.) and TOP-CW grant (714.017.003) (A.P. and W.V.) from the Netherlands Organization for Scientific Research. Oncode Institute is partly financed by the Dutch Cancer Society. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = feb,

day = "21",

doi = "10.1038/s41467-022-28642-9",

language = "English",

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journal = "Nature Communications",

issn = "2041-1723",

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T1 - Global and transcription-coupled repair of 8-oxoG is initiated by nucleotide excision repair proteins

AU - Kumar, Namrata

AU - Theil, Arjan F.

AU - Roginskaya, Vera

AU - Ali, Yasmin

AU - Calderon, Michael

AU - Watkins, Simon C.

AU - Barnes, Ryan P.

AU - Opresko, Patricia L.

AU - Pines, Alex

AU - Lans, Hannes

AU - Vermeulen, Wim

AU - Van Houten, Bennett

N1 - Funding Information: We wish to thank Dr. Elise Fouquerel for the U2OS-FAP-TRF1 cell line. We thank Dr. Marcel P. Bruchez for providing the MG-2I and 660 nm light source. We thank Dr. Jacob Stuart-Ornstein, Dr. Roderick O’Sullivan, and Dr. Karen Arndt for helpful discussions. We also thank our lab members, Dr. Matt Schaich, Sripriya Raja, Dr. Wei Qian, Dr. Zhou Zhong and Brittani Schnable for careful reading of the manuscript. We are thankful to Dr. Jean Cadet for discussions regarding 8-oxoG lesion frequencies. Funding sources: This work was supported by NIH grants, R01ES019566, R01ES028686, and R35ES031638 (B.V.H.), R35ES030396 (P.L.O.), F32AG067710 (R.P.B.), the gravitation program CancerGenomiCs.nl (H.L., A.P., and W.V.) and TOP-CW grant (714.017.003) (A.P. and W.V.) from the Netherlands Organization for Scientific Research. Oncode Institute is partly financed by the Dutch Cancer Society. Publisher Copyright: © 2022, The Author(s).

PY - 2022/2/21

Y1 - 2022/2/21

N2 - UV-DDB, consisting of subunits DDB1 and DDB2, recognizes UV-induced photoproducts during global genome nucleotide excision repair (GG-NER). We recently demonstrated a noncanonical role of UV-DDB in stimulating base excision repair (BER) which raised several questions about the timing of UV-DDB arrival at 8-oxoguanine (8-oxoG), and the dependency of UV-DDB on the recruitment of downstream BER and NER proteins. Using two different approaches to introduce 8-oxoG in cells, we show that DDB2 is recruited to 8-oxoG immediately after damage and colocalizes with 8-oxoG glycosylase (OGG1) at sites of repair. 8-oxoG removal and OGG1 recruitment is significantly reduced in the absence of DDB2. NER proteins, XPA and XPC, also accumulate at 8-oxoG. While XPC recruitment is dependent on DDB2, XPA recruitment is DDB2-independent and transcription-coupled. Finally, DDB2 accumulation at 8-oxoG induces local chromatin unfolding. We propose that DDB2-mediated chromatin decompaction facilitates the recruitment of downstream BER proteins to 8-oxoG lesions.

AB - UV-DDB, consisting of subunits DDB1 and DDB2, recognizes UV-induced photoproducts during global genome nucleotide excision repair (GG-NER). We recently demonstrated a noncanonical role of UV-DDB in stimulating base excision repair (BER) which raised several questions about the timing of UV-DDB arrival at 8-oxoguanine (8-oxoG), and the dependency of UV-DDB on the recruitment of downstream BER and NER proteins. Using two different approaches to introduce 8-oxoG in cells, we show that DDB2 is recruited to 8-oxoG immediately after damage and colocalizes with 8-oxoG glycosylase (OGG1) at sites of repair. 8-oxoG removal and OGG1 recruitment is significantly reduced in the absence of DDB2. NER proteins, XPA and XPC, also accumulate at 8-oxoG. While XPC recruitment is dependent on DDB2, XPA recruitment is DDB2-independent and transcription-coupled. Finally, DDB2 accumulation at 8-oxoG induces local chromatin unfolding. We propose that DDB2-mediated chromatin decompaction facilitates the recruitment of downstream BER proteins to 8-oxoG lesions.

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DO - 10.1038/s41467-022-28642-9

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SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

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ER -

Global and transcription-coupled repair of 8-oxoG is initiated by nucleotide excision repair proteins

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