XPC–PARP complexes engage the chromatin remodeler ALC1 to catalyze global genome DNA damage repair

Charlotte Blessing, Katja Apelt, Diana van den Heuvel, Claudia Gonzalez-Leal, Magdalena B. Rother, Melanie van der Woude, Román González-Prieto, Adi Yifrach, Avital Parnas, Rashmi G. Shah, Tia Tyrsett Kuo, Daphne E.C. Boer, Jin Cai, Angela Kragten, Hyun Suk Kim, Orlando D. Schärer, Alfred C.O. Vertegaal, Girish M. Shah, Sheera Adar, Hannes LansHaico van Attikum, Andreas G. Ladurner*, Martijn S. Luijsterburg

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Cells employ global genome nucleotide excision repair (GGR) to eliminate a broad spectrum of DNA lesions, including those induced by UV light. The lesion-recognition factor XPC initiates repair of helix-destabilizing DNA lesions, but binds poorly to lesions such as CPDs that do not destabilize DNA. How difficult-to-repair lesions are detected in chromatin is unknown. Here, we identify the poly-(ADP-ribose) polymerases PARP1 and PARP2 as constitutive interactors of XPC. Their interaction results in the XPC-stimulated synthesis of poly-(ADP-ribose) (PAR) by PARP1 at UV lesions, which in turn enables the recruitment and activation of the PAR-regulated chromatin remodeler ALC1. PARP2, on the other hand, modulates the retention of ALC1 at DNA damage sites. Notably, ALC1 mediates chromatin expansion at UV-induced DNA lesions, leading to the timely clearing of CPD lesions. Thus, we reveal how chromatin containing difficult-to-repair DNA lesions is primed for repair, providing insight into mechanisms of chromatin plasticity during GGR.

Original languageEnglish
Article number4762
JournalNature Communications
Volume13
Issue number1
DOIs
Publication statusPublished - 13 Aug 2022

Bibliographical note

Funding Information:
The authors acknowledge Sylvie Noordermeer for the PARP inhibitor olaparib. We thank Artur Mayerhofer for kindly providing the Stratalinker UV device for irradiation. We thank Nicholas Lakin for providing PARP1-KO and PARP2-KO cells. We thank Susan Janicki for providing U2OS 2-6-3 cells. C. elegans strains were provided by the Caenorhabditis Genetics Center (funded by NIH Office of Research Infrastructure Programs P40 OD010440). We thank Masanao Miwa (National Cancer Center Research Institute, Tokyo) for providing 10H hybridoma cells obtained through the Riken cell bank. We thank Mihaela Robu for feedback on the manuscript. This research was supported by an LUMC Research Fellowship, ENW-M (OCENW.KLEIN.090), and ALW-VIDI grants (ALW.016.161.320) from the Dutch Research Council (NWO) to M.S.L. This research was further funded by the DFG (German Research Foundation) through Project-ID 213249687 - SFB 1064 and Project-ID 325871075 - SFB 1309, as well as LMU to A.G.L. C.B. was the recipient of a grant from the Stiftungskommission of the LMU Medical Faculty. R.G-P was the recipient of a Young Investigator Grant from the Dutch Cancer Society (KWF-YIG 11367). A.C.O.V. was funded by an ERC grant (310913). H.L. and M.v.d.W. were funded by the Netherlands Organization for Scientific Research (711.018.007 and CancerGenomiCs.nl) and the Oncode Institute, which is partly financed by the Dutch Cancer Society. O.D.S. was supported by the Korean Institute of Basic Science (IBS-R022-A1) and the National Cancer Insitute (USA, P01-CA092584). G.M.S. was supported by grants from the Research Centre of CHU de Quebec Laval University as well as from the Natural Sciences and Engineering Research Council of Canada through the Discovery Grant (RGPIN-2016-05868) and the Discovery Accelerator Supplement Grant (RGPAS-492875-2016). S.A. was funded by the Israel Cancer Research Fund Research Career Development Award (3013004741), the Israel Cancer Association grant (20210078), and Israel Science Foundation grant (1710/17) administered by the Israeli Academy of Science and Humanities and is the recipient of the Jacob and Lena Joels memorial senior lectureship. H.v.A. was funded by a VICI grant from the Dutch Research Council (NWO-VICI grant VI.C.182.052).

Funding Information:
The authors acknowledge Sylvie Noordermeer for the PARP inhibitor olaparib. We thank Artur Mayerhofer for kindly providing the Stratalinker UV device for irradiation. We thank Nicholas Lakin for providing PARP1-KO and PARP2-KO cells. We thank Susan Janicki for providing U2OS 2-6-3 cells. C. elegans strains were provided by the Caenorhabditis Genetics Center (funded by NIH Office of Research Infrastructure Programs P40 OD010440). We thank Masanao Miwa (National Cancer Center Research Institute, Tokyo) for providing 10H hybridoma cells obtained through the Riken cell bank. We thank Mihaela Robu for feedback on the manuscript. This research was supported by an LUMC Research Fellowship, ENW-M (OCENW.KLEIN.090), and ALW-VIDI grants (ALW.016.161.320) from the Dutch Research Council (NWO) to M.S.L. This research was further funded by the DFG (German Research Foundation) through Project-ID 213249687 - SFB 1064 and Project-ID 325871075 - SFB 1309, as well as LMU to A.G.L. C.B. was the recipient of a grant from the Stiftungskommission of the LMU Medical Faculty. R.G-P was the recipient of a Young Investigator Grant from the Dutch Cancer Society (KWF-YIG 11367). A.C.O.V. was funded by an ERC grant (310913). H.L. and M.v.d.W. were funded by the Netherlands Organization for Scientific Research (711.018.007 and CancerGenomiCs.nl) and the Oncode Institute, which is partly financed by the Dutch Cancer Society. O.D.S. was supported by the Korean Institute of Basic Science (IBS-R022-A1) and the National Cancer Insitute (USA, P01-CA092584). G.M.S. was supported by grants from the Research Centre of CHU de Quebec Laval University as well as from the Natural Sciences and Engineering Research Council of Canada through the Discovery Grant (RGPIN-2016-05868) and the Discovery Accelerator Supplement Grant (RGPAS-492875-2016). S.A. was funded by the Israel Cancer Research Fund Research Career Development Award (3013004741), the Israel Cancer Association grant (20210078), and Israel Science Foundation grant (1710/17) administered by the Israeli Academy of Science and Humanities and is the recipient of the Jacob and Lena Joels memorial senior lectureship. H.v.A. was funded by a VICI grant from the Dutch Research Council (NWO-VICI grant VI.C.182.052).

Publisher Copyright:
© 2022, The Author(s).

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