Histone H1 couples initiation and amplification of ubiquitin signalling after DNA damage

Research output: Contribution to journalLetterResearchpeer-review

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Histone H1 couples initiation and amplification of ubiquitin signalling after DNA damage. / Thorslund, Tina; Ripplinger, Anita; Hoffmann, Saskia; Wild, Thomas; Uckelmann, Michael; Villumsen, Bine; Narita, Takeo; Sixma, Titia K; Choudhary, Chuna Ram; Bekker-Jensen, Simon; Mailand, Niels.

In: Nature, Vol. 527, No. 7578, 19.11.2015, p. 389-93.

Research output: Contribution to journalLetterResearchpeer-review

Harvard

Thorslund, T, Ripplinger, A, Hoffmann, S, Wild, T, Uckelmann, M, Villumsen, B, Narita, T, Sixma, TK, Choudhary, CR, Bekker-Jensen, S & Mailand, N 2015, 'Histone H1 couples initiation and amplification of ubiquitin signalling after DNA damage', Nature, vol. 527, no. 7578, pp. 389-93. https://doi.org/10.1038/nature15401

APA

Thorslund, T., Ripplinger, A., Hoffmann, S., Wild, T., Uckelmann, M., Villumsen, B., ... Mailand, N. (2015). Histone H1 couples initiation and amplification of ubiquitin signalling after DNA damage. Nature, 527(7578), 389-93. https://doi.org/10.1038/nature15401

Vancouver

Thorslund T, Ripplinger A, Hoffmann S, Wild T, Uckelmann M, Villumsen B et al. Histone H1 couples initiation and amplification of ubiquitin signalling after DNA damage. Nature. 2015 Nov 19;527(7578):389-93. https://doi.org/10.1038/nature15401

Author

Thorslund, Tina ; Ripplinger, Anita ; Hoffmann, Saskia ; Wild, Thomas ; Uckelmann, Michael ; Villumsen, Bine ; Narita, Takeo ; Sixma, Titia K ; Choudhary, Chuna Ram ; Bekker-Jensen, Simon ; Mailand, Niels. / Histone H1 couples initiation and amplification of ubiquitin signalling after DNA damage. In: Nature. 2015 ; Vol. 527, No. 7578. pp. 389-93.

Bibtex

@article{1e5b08be43054b11ab79c1e4c9c0cd1c,
title = "Histone H1 couples initiation and amplification of ubiquitin signalling after DNA damage",
abstract = "DNA double-strand breaks (DSBs) are highly cytotoxic DNA lesions that trigger non-proteolytic ubiquitylation of adjacent chromatin areas to generate binding sites for DNA repair factors. This depends on the sequential actions of the E3 ubiquitin ligases RNF8 and RNF168 (refs 1-6), and UBC13 (also known as UBE2N), an E2 ubiquitin-conjugating enzyme that specifically generates K63-linked ubiquitin chains. Whereas RNF168 is known to catalyse ubiquitylation of H2A-type histones, leading to the recruitment of repair factors such as 53BP1 (refs 8-10), the critical substrates of RNF8 and K63-linked ubiquitylation remain elusive. Here we elucidate how RNF8 and UBC13 promote recruitment of RNF168 and downstream factors to DSB sites in human cells. We establish that UBC13-dependent K63-linked ubiquitylation at DSB sites is predominantly mediated by RNF8 but not RNF168, and that H1-type linker histones, but not core histones, represent major chromatin-associated targets of this modification. The RNF168 module (UDM1) recognizing RNF8-generated ubiquitylations is a high-affinity reader of K63-ubiquitylated H1, mechanistically explaining the essential roles of RNF8 and UBC13 in recruiting RNF168 to DSBs. Consistently, reduced expression or chromatin association of linker histones impair accumulation of K63-linked ubiquitin conjugates and repair factors at DSB-flanking chromatin. These results identify histone H1 as a key target of RNF8-UBC13 in DSB signalling and expand the concept of the histone code by showing that posttranslational modifications of linker histones can serve as important marks for recognition by factors involved in genome stability maintenance, and possibly beyond.",
keywords = "Chromatin, DNA Breaks, Double-Stranded, DNA Damage, DNA Repair, DNA-Binding Proteins, Histones, Humans, Lysine, Protein Structure, Tertiary, Signal Transduction, Ubiquitin, Ubiquitin-Conjugating Enzymes, Ubiquitin-Protein Ligases, Ubiquitination",
author = "Tina Thorslund and Anita Ripplinger and Saskia Hoffmann and Thomas Wild and Michael Uckelmann and Bine Villumsen and Takeo Narita and Sixma, {Titia K} and Choudhary, {Chuna Ram} and Simon Bekker-Jensen and Niels Mailand",
year = "2015",
month = "11",
day = "19",
doi = "10.1038/nature15401",
language = "English",
volume = "527",
pages = "389--93",
journal = "Nature",
issn = "0028-0836",
publisher = "nature publishing group",
number = "7578",

}

RIS

TY - JOUR

T1 - Histone H1 couples initiation and amplification of ubiquitin signalling after DNA damage

AU - Thorslund, Tina

AU - Ripplinger, Anita

AU - Hoffmann, Saskia

AU - Wild, Thomas

AU - Uckelmann, Michael

AU - Villumsen, Bine

AU - Narita, Takeo

AU - Sixma, Titia K

AU - Choudhary, Chuna Ram

AU - Bekker-Jensen, Simon

AU - Mailand, Niels

PY - 2015/11/19

Y1 - 2015/11/19

N2 - DNA double-strand breaks (DSBs) are highly cytotoxic DNA lesions that trigger non-proteolytic ubiquitylation of adjacent chromatin areas to generate binding sites for DNA repair factors. This depends on the sequential actions of the E3 ubiquitin ligases RNF8 and RNF168 (refs 1-6), and UBC13 (also known as UBE2N), an E2 ubiquitin-conjugating enzyme that specifically generates K63-linked ubiquitin chains. Whereas RNF168 is known to catalyse ubiquitylation of H2A-type histones, leading to the recruitment of repair factors such as 53BP1 (refs 8-10), the critical substrates of RNF8 and K63-linked ubiquitylation remain elusive. Here we elucidate how RNF8 and UBC13 promote recruitment of RNF168 and downstream factors to DSB sites in human cells. We establish that UBC13-dependent K63-linked ubiquitylation at DSB sites is predominantly mediated by RNF8 but not RNF168, and that H1-type linker histones, but not core histones, represent major chromatin-associated targets of this modification. The RNF168 module (UDM1) recognizing RNF8-generated ubiquitylations is a high-affinity reader of K63-ubiquitylated H1, mechanistically explaining the essential roles of RNF8 and UBC13 in recruiting RNF168 to DSBs. Consistently, reduced expression or chromatin association of linker histones impair accumulation of K63-linked ubiquitin conjugates and repair factors at DSB-flanking chromatin. These results identify histone H1 as a key target of RNF8-UBC13 in DSB signalling and expand the concept of the histone code by showing that posttranslational modifications of linker histones can serve as important marks for recognition by factors involved in genome stability maintenance, and possibly beyond.

AB - DNA double-strand breaks (DSBs) are highly cytotoxic DNA lesions that trigger non-proteolytic ubiquitylation of adjacent chromatin areas to generate binding sites for DNA repair factors. This depends on the sequential actions of the E3 ubiquitin ligases RNF8 and RNF168 (refs 1-6), and UBC13 (also known as UBE2N), an E2 ubiquitin-conjugating enzyme that specifically generates K63-linked ubiquitin chains. Whereas RNF168 is known to catalyse ubiquitylation of H2A-type histones, leading to the recruitment of repair factors such as 53BP1 (refs 8-10), the critical substrates of RNF8 and K63-linked ubiquitylation remain elusive. Here we elucidate how RNF8 and UBC13 promote recruitment of RNF168 and downstream factors to DSB sites in human cells. We establish that UBC13-dependent K63-linked ubiquitylation at DSB sites is predominantly mediated by RNF8 but not RNF168, and that H1-type linker histones, but not core histones, represent major chromatin-associated targets of this modification. The RNF168 module (UDM1) recognizing RNF8-generated ubiquitylations is a high-affinity reader of K63-ubiquitylated H1, mechanistically explaining the essential roles of RNF8 and UBC13 in recruiting RNF168 to DSBs. Consistently, reduced expression or chromatin association of linker histones impair accumulation of K63-linked ubiquitin conjugates and repair factors at DSB-flanking chromatin. These results identify histone H1 as a key target of RNF8-UBC13 in DSB signalling and expand the concept of the histone code by showing that posttranslational modifications of linker histones can serve as important marks for recognition by factors involved in genome stability maintenance, and possibly beyond.

KW - Chromatin

KW - DNA Breaks, Double-Stranded

KW - DNA Damage

KW - DNA Repair

KW - DNA-Binding Proteins

KW - Histones

KW - Humans

KW - Lysine

KW - Protein Structure, Tertiary

KW - Signal Transduction

KW - Ubiquitin

KW - Ubiquitin-Conjugating Enzymes

KW - Ubiquitin-Protein Ligases

KW - Ubiquitination

U2 - 10.1038/nature15401

DO - 10.1038/nature15401

M3 - Letter

VL - 527

SP - 389

EP - 393

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7578

ER -

ID: 152957186