A ubiquitin-dependent signalling axis specific for ALKBH-mediated DNA dealkylation repair

Joshua R. Brickner, Jennifer M. Soll, Patrick M. Lombardi, Cathrine B. Vågbø, Miranda C. Mudge, Clement Oyeniran, Renana Rabe, Jessica Jackson, Meagan E. Sullender, Elyse Blazosky, Andrea K. Byrum, Yu Zhao, Mark A. Corbett, Jozef Gécz, Michael Field, Alessandro Vindigni, Geir Slupphaug, Cynthia Wolberger, Nima Mosammaparast

Research output: Contribution to journalArticle

Abstract

DNA repair is essential to prevent the cytotoxic or mutagenic effects of various types of DNA lesions, which are sensed by distinct pathways to recruit repair factors specific to the damage type. Although biochemical mechanisms for repairing several forms of genomic insults are well understood, the upstream signalling pathways that trigger repair are established for only certain types of damage, such as double-stranded breaks and interstrand crosslinks. Understanding the upstream signalling events that mediate recognition and repair of DNA alkylation damage is particularly important, since alkylation chemotherapy is one of the most widely used systemic modalities for cancer treatment and because environmental chemicals may trigger DNA alkylation. Here we demonstrate that human cells have a previously unrecognized signalling mechanism for sensing damage induced by alkylation. We find that the alkylation repair complex ASCC (activating signal cointegrator complex) relocalizes to distinct nuclear foci specifically upon exposure of cells to alkylating agents. These foci associate with alkylated nucleotides, and coincide spatially with elongating RNA polymerase II and splicing components. Proper recruitment of the repair complex requires recognition of K63-linked polyubiquitin by the CUE (coupling of ubiquitin conjugation to ER degradation) domain of the subunit ASCC2. Loss of this subunit impedes alkylation adduct repair kinetics and increases sensitivity to alkylating agents, but not other forms of DNA damage. We identify RING finger protein 113A (RNF113A) as the E3 ligase responsible for upstream ubiquitin signalling in the ASCC pathway. Cells from patients with X-linked trichothiodystrophy, which harbour a mutation in RNF113A, are defective in ASCC foci formation and are hypersensitive to alkylating agents. Together, our work reveals a previously unrecognized ubiquitin-dependent pathway induced specifically to repair alkylation damage, shedding light on the molecular mechanism of X-linked trichothiodystrophy.

Original languageEnglish (US)
Pages (from-to)389-393
Number of pages5
JournalNature
Volume551
Issue number7680
DOIs
StatePublished - Nov 16 2017

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Dealkylation
Alkylation
Ubiquitin
DNA Repair
Alkylating Agents
Trichothiodystrophy Syndromes
DNA Damage
Polyubiquitin
RNA Splicing
Ubiquitin-Protein Ligases
RNA Polymerase II
DNA
Proteins
Nucleotides
Drug Therapy
Mutation

ASJC Scopus subject areas

  • General

Cite this

Brickner, J. R., Soll, J. M., Lombardi, P. M., Vågbø, C. B., Mudge, M. C., Oyeniran, C., ... Mosammaparast, N. (2017). A ubiquitin-dependent signalling axis specific for ALKBH-mediated DNA dealkylation repair. Nature, 551(7680), 389-393. https://doi.org/10.1038/nature24484

A ubiquitin-dependent signalling axis specific for ALKBH-mediated DNA dealkylation repair. / Brickner, Joshua R.; Soll, Jennifer M.; Lombardi, Patrick M.; Vågbø, Cathrine B.; Mudge, Miranda C.; Oyeniran, Clement; Rabe, Renana; Jackson, Jessica; Sullender, Meagan E.; Blazosky, Elyse; Byrum, Andrea K.; Zhao, Yu; Corbett, Mark A.; Gécz, Jozef; Field, Michael; Vindigni, Alessandro; Slupphaug, Geir; Wolberger, Cynthia; Mosammaparast, Nima.

In: Nature, Vol. 551, No. 7680, 16.11.2017, p. 389-393.

Research output: Contribution to journalArticle

Brickner, JR, Soll, JM, Lombardi, PM, Vågbø, CB, Mudge, MC, Oyeniran, C, Rabe, R, Jackson, J, Sullender, ME, Blazosky, E, Byrum, AK, Zhao, Y, Corbett, MA, Gécz, J, Field, M, Vindigni, A, Slupphaug, G, Wolberger, C & Mosammaparast, N 2017, 'A ubiquitin-dependent signalling axis specific for ALKBH-mediated DNA dealkylation repair', Nature, vol. 551, no. 7680, pp. 389-393. https://doi.org/10.1038/nature24484
Brickner JR, Soll JM, Lombardi PM, Vågbø CB, Mudge MC, Oyeniran C et al. A ubiquitin-dependent signalling axis specific for ALKBH-mediated DNA dealkylation repair. Nature. 2017 Nov 16;551(7680):389-393. https://doi.org/10.1038/nature24484
Brickner, Joshua R. ; Soll, Jennifer M. ; Lombardi, Patrick M. ; Vågbø, Cathrine B. ; Mudge, Miranda C. ; Oyeniran, Clement ; Rabe, Renana ; Jackson, Jessica ; Sullender, Meagan E. ; Blazosky, Elyse ; Byrum, Andrea K. ; Zhao, Yu ; Corbett, Mark A. ; Gécz, Jozef ; Field, Michael ; Vindigni, Alessandro ; Slupphaug, Geir ; Wolberger, Cynthia ; Mosammaparast, Nima. / A ubiquitin-dependent signalling axis specific for ALKBH-mediated DNA dealkylation repair. In: Nature. 2017 ; Vol. 551, No. 7680. pp. 389-393.
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