Unrestrained poly-ADP-ribosylation provides insights into chromatin regulation and human disease

Research output: Contribution to journal › Journal article › Research › peer-review

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Unrestrained poly-ADP-ribosylation provides insights into chromatin regulation and human disease. / Prokhorova, Evgeniia; Agnew, Thomas; Wondisford, Anne R; Tellier, Michael; Kaminski, Nicole; Beijer, Danique; Holder, James; Groslambert, Josephine; Suskiewicz, Marcin J; Zhu, Kang; Reber, Julia M; Krassnig, Sarah C; Palazzo, Luca; Murphy, Shona; Nielsen, Michael L; Mangerich, Aswin; Ahel, Dragana; Baets, Jonathan; O'Sullivan, Roderick J; Ahel, Ivan.

In: Molecular Cell, Vol. 81, No. 12, 2021, p. 2640-2655.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Prokhorova, E, Agnew, T, Wondisford, AR, Tellier, M, Kaminski, N, Beijer, D, Holder, J, Groslambert, J, Suskiewicz, MJ, Zhu, K, Reber, JM, Krassnig, SC, Palazzo, L, Murphy, S, Nielsen, ML, Mangerich, A, Ahel, D, Baets, J, O'Sullivan, RJ & Ahel, I 2021, 'Unrestrained poly-ADP-ribosylation provides insights into chromatin regulation and human disease', Molecular Cell, vol. 81, no. 12, pp. 2640-2655. https://doi.org/10.1016/j.molcel.2021.04.028

APA

Prokhorova, E., Agnew, T., Wondisford, A. R., Tellier, M., Kaminski, N., Beijer, D., Holder, J., Groslambert, J., Suskiewicz, M. J., Zhu, K., Reber, J. M., Krassnig, S. C., Palazzo, L., Murphy, S., Nielsen, M. L., Mangerich, A., Ahel, D., Baets, J., O'Sullivan, R. J., & Ahel, I. (2021). Unrestrained poly-ADP-ribosylation provides insights into chromatin regulation and human disease. Molecular Cell, 81(12), 2640-2655. https://doi.org/10.1016/j.molcel.2021.04.028

Vancouver

Prokhorova E, Agnew T, Wondisford AR, Tellier M, Kaminski N, Beijer D et al. Unrestrained poly-ADP-ribosylation provides insights into chromatin regulation and human disease. Molecular Cell. 2021;81(12):2640-2655. https://doi.org/10.1016/j.molcel.2021.04.028

Author

Prokhorova, Evgeniia ; Agnew, Thomas ; Wondisford, Anne R ; Tellier, Michael ; Kaminski, Nicole ; Beijer, Danique ; Holder, James ; Groslambert, Josephine ; Suskiewicz, Marcin J ; Zhu, Kang ; Reber, Julia M ; Krassnig, Sarah C ; Palazzo, Luca ; Murphy, Shona ; Nielsen, Michael L ; Mangerich, Aswin ; Ahel, Dragana ; Baets, Jonathan ; O'Sullivan, Roderick J ; Ahel, Ivan. / Unrestrained poly-ADP-ribosylation provides insights into chromatin regulation and human disease. In: Molecular Cell. 2021 ; Vol. 81, No. 12. pp. 2640-2655.

Bibtex

@article{c20419d0064842858385b15effb62f99,

title = "Unrestrained poly-ADP-ribosylation provides insights into chromatin regulation and human disease",

abstract = "ARH3/ADPRHL2 and PARG are the primary enzymes reversing ADP-ribosylation in vertebrates, yet their functions in vivo remain unclear. ARH3 is the only hydrolase able to remove serine-linked mono(ADP-ribose) (MAR) but is much less efficient than PARG against poly(ADP-ribose) (PAR) chains in vitro. Here, by using ARH3-deficient cells, we demonstrate that endogenous MARylation persists on chromatin throughout the cell cycle, including mitosis, and is surprisingly well tolerated. Conversely, persistent PARylation is highly toxic and has distinct physiological effects, in particular on active transcription histone marks such as H3K9ac and H3K27ac. Furthermore, we reveal a synthetic lethal interaction between ARH3 and PARG and identify loss of ARH3 as a mechanism of PARP inhibitor resistance, both of which can be exploited in cancer therapy. Finally, we extend our findings to neurodegeneration, suggesting that patients with inherited ARH3 deficiency suffer from stress-induced pathogenic increase in PARylation that can be mitigated by PARP inhibition.",

author = "Evgeniia Prokhorova and Thomas Agnew and Wondisford, {Anne R} and Michael Tellier and Nicole Kaminski and Danique Beijer and James Holder and Josephine Groslambert and Suskiewicz, {Marcin J} and Kang Zhu and Reber, {Julia M} and Krassnig, {Sarah C} and Luca Palazzo and Shona Murphy and Nielsen, {Michael L} and Aswin Mangerich and Dragana Ahel and Jonathan Baets and O'Sullivan, {Roderick J} and Ivan Ahel",

year = "2021",

doi = "10.1016/j.molcel.2021.04.028",

language = "English",

volume = "81",

pages = "2640--2655",

journal = "Molecular Cell",

issn = "1097-2765",

publisher = "Cell Press",

number = "12",

}

RIS

TY - JOUR

T1 - Unrestrained poly-ADP-ribosylation provides insights into chromatin regulation and human disease

AU - Prokhorova, Evgeniia

AU - Agnew, Thomas

AU - Wondisford, Anne R

AU - Tellier, Michael

AU - Kaminski, Nicole

AU - Beijer, Danique

AU - Holder, James

AU - Groslambert, Josephine

AU - Suskiewicz, Marcin J

AU - Zhu, Kang

AU - Reber, Julia M

AU - Krassnig, Sarah C

AU - Palazzo, Luca

AU - Murphy, Shona

AU - Nielsen, Michael L

AU - Mangerich, Aswin

AU - Ahel, Dragana

AU - Baets, Jonathan

AU - O'Sullivan, Roderick J

AU - Ahel, Ivan

PY - 2021

Y1 - 2021

N2 - ARH3/ADPRHL2 and PARG are the primary enzymes reversing ADP-ribosylation in vertebrates, yet their functions in vivo remain unclear. ARH3 is the only hydrolase able to remove serine-linked mono(ADP-ribose) (MAR) but is much less efficient than PARG against poly(ADP-ribose) (PAR) chains in vitro. Here, by using ARH3-deficient cells, we demonstrate that endogenous MARylation persists on chromatin throughout the cell cycle, including mitosis, and is surprisingly well tolerated. Conversely, persistent PARylation is highly toxic and has distinct physiological effects, in particular on active transcription histone marks such as H3K9ac and H3K27ac. Furthermore, we reveal a synthetic lethal interaction between ARH3 and PARG and identify loss of ARH3 as a mechanism of PARP inhibitor resistance, both of which can be exploited in cancer therapy. Finally, we extend our findings to neurodegeneration, suggesting that patients with inherited ARH3 deficiency suffer from stress-induced pathogenic increase in PARylation that can be mitigated by PARP inhibition.

AB - ARH3/ADPRHL2 and PARG are the primary enzymes reversing ADP-ribosylation in vertebrates, yet their functions in vivo remain unclear. ARH3 is the only hydrolase able to remove serine-linked mono(ADP-ribose) (MAR) but is much less efficient than PARG against poly(ADP-ribose) (PAR) chains in vitro. Here, by using ARH3-deficient cells, we demonstrate that endogenous MARylation persists on chromatin throughout the cell cycle, including mitosis, and is surprisingly well tolerated. Conversely, persistent PARylation is highly toxic and has distinct physiological effects, in particular on active transcription histone marks such as H3K9ac and H3K27ac. Furthermore, we reveal a synthetic lethal interaction between ARH3 and PARG and identify loss of ARH3 as a mechanism of PARP inhibitor resistance, both of which can be exploited in cancer therapy. Finally, we extend our findings to neurodegeneration, suggesting that patients with inherited ARH3 deficiency suffer from stress-induced pathogenic increase in PARylation that can be mitigated by PARP inhibition.

U2 - 10.1016/j.molcel.2021.04.028

DO - 10.1016/j.molcel.2021.04.028

M3 - Journal article

C2 - 34019811

VL - 81

SP - 2640

EP - 2655

JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

IS - 12

ER -

ID: 271974309