The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage.

Grant Stewart; S Panier; Kelly Townsend; AK Al-Hakim; NK Kolas; Edward Miller; S Nakada; J Ylanko; S Olivarius; M Mendez; Ceri Oldreive; J Wildenhain; A Tagliaferro; L Pelletier; N Taubenheim; A Durandy; Philip Byrd; Tatjana Stankovic; Alexander Taylor; D Durocher

doi:10.1016/j.cell.2008.12.042

The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage.

Grant Stewart, S Panier, Kelly Townsend, AK Al-Hakim, NK Kolas, Edward Miller, S Nakada, J Ylanko, S Olivarius, M Mendez, Ceri Oldreive, J Wildenhain, A Tagliaferro, L Pelletier, N Taubenheim, A Durandy, Philip Byrd, Tatjana Stankovic, Alexander Taylor, D Durocher

Cancer and Genomic Sciences

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Abstract

The biological response to DNA double-strand breaks acts to preserve genome integrity. Individuals bearing inactivating mutations in components of this response exhibit clinical symptoms that include cellular radiosensitivity, immunodeficiency, and cancer predisposition. The archetype for such disorders is Ataxia-Telangiectasia caused by biallelic mutation in ATM, a central component of the DNA damage response. Here, we report that the ubiquitin ligase RNF168 is mutated in the RIDDLE syndrome, a recently discovered immunodeficiency and radiosensitivity disorder. We show that RNF168 is recruited to sites of DNA damage by binding to ubiquitylated histone H2A. RNF168 acts with UBC13 to amplify the RNF8-dependent histone ubiquitylation by targeting H2A-type histones and by promoting the formation of lysine 63-linked ubiquitin conjugates. These RNF168-dependent chromatin modifications orchestrate the accumulation of 53BP1 and BRCA1 to DNA lesions, and their loss is the likely cause of the cellular and developmental phenotypes associated with RIDDLE syndrome.

Original language	English
Pages (from-to)	420-34
Number of pages	15
Journal	Cell
Volume	136
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2008.12.042
Publication status	Published - 6 Feb 2009

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Stewart, G., Panier, S., Townsend, K., Al-Hakim, AK., Kolas, NK., Miller, E., Nakada, S., Ylanko, J., Olivarius, S., Mendez, M., Oldreive, C., Wildenhain, J., Tagliaferro, A., Pelletier, L., Taubenheim, N., Durandy, A., Byrd, P., Stankovic, T., Taylor, A., & Durocher, D. (2009). The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage. Cell, 136(3), 420-34. https://doi.org/10.1016/j.cell.2008.12.042

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title = "The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage.",

abstract = "The biological response to DNA double-strand breaks acts to preserve genome integrity. Individuals bearing inactivating mutations in components of this response exhibit clinical symptoms that include cellular radiosensitivity, immunodeficiency, and cancer predisposition. The archetype for such disorders is Ataxia-Telangiectasia caused by biallelic mutation in ATM, a central component of the DNA damage response. Here, we report that the ubiquitin ligase RNF168 is mutated in the RIDDLE syndrome, a recently discovered immunodeficiency and radiosensitivity disorder. We show that RNF168 is recruited to sites of DNA damage by binding to ubiquitylated histone H2A. RNF168 acts with UBC13 to amplify the RNF8-dependent histone ubiquitylation by targeting H2A-type histones and by promoting the formation of lysine 63-linked ubiquitin conjugates. These RNF168-dependent chromatin modifications orchestrate the accumulation of 53BP1 and BRCA1 to DNA lesions, and their loss is the likely cause of the cellular and developmental phenotypes associated with RIDDLE syndrome.",

author = "Grant Stewart and S Panier and Kelly Townsend and AK Al-Hakim and NK Kolas and Edward Miller and S Nakada and J Ylanko and S Olivarius and M Mendez and Ceri Oldreive and J Wildenhain and A Tagliaferro and L Pelletier and N Taubenheim and A Durandy and Philip Byrd and Tatjana Stankovic and Alexander Taylor and D Durocher",

year = "2009",

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doi = "10.1016/j.cell.2008.12.042",

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Stewart, G, Panier, S, Townsend, K, Al-Hakim, AK, Kolas, NK, Miller, E, Nakada, S, Ylanko, J, Olivarius, S, Mendez, M, Oldreive, C, Wildenhain, J, Tagliaferro, A, Pelletier, L, Taubenheim, N, Durandy, A, Byrd, P, Stankovic, T , Taylor, A & Durocher, D 2009, 'The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage.', Cell, vol. 136, no. 3, pp. 420-34. https://doi.org/10.1016/j.cell.2008.12.042

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T1 - The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage.

AU - Stewart, Grant

AU - Panier, S

AU - Townsend, Kelly

AU - Al-Hakim, AK

AU - Kolas, NK

AU - Miller, Edward

AU - Nakada, S

AU - Ylanko, J

AU - Olivarius, S

AU - Mendez, M

AU - Oldreive, Ceri

AU - Wildenhain, J

AU - Tagliaferro, A

AU - Pelletier, L

AU - Taubenheim, N

AU - Durandy, A

AU - Byrd, Philip

AU - Stankovic, Tatjana

AU - Taylor, Alexander

AU - Durocher, D

PY - 2009/2/6

Y1 - 2009/2/6

N2 - The biological response to DNA double-strand breaks acts to preserve genome integrity. Individuals bearing inactivating mutations in components of this response exhibit clinical symptoms that include cellular radiosensitivity, immunodeficiency, and cancer predisposition. The archetype for such disorders is Ataxia-Telangiectasia caused by biallelic mutation in ATM, a central component of the DNA damage response. Here, we report that the ubiquitin ligase RNF168 is mutated in the RIDDLE syndrome, a recently discovered immunodeficiency and radiosensitivity disorder. We show that RNF168 is recruited to sites of DNA damage by binding to ubiquitylated histone H2A. RNF168 acts with UBC13 to amplify the RNF8-dependent histone ubiquitylation by targeting H2A-type histones and by promoting the formation of lysine 63-linked ubiquitin conjugates. These RNF168-dependent chromatin modifications orchestrate the accumulation of 53BP1 and BRCA1 to DNA lesions, and their loss is the likely cause of the cellular and developmental phenotypes associated with RIDDLE syndrome.

AB - The biological response to DNA double-strand breaks acts to preserve genome integrity. Individuals bearing inactivating mutations in components of this response exhibit clinical symptoms that include cellular radiosensitivity, immunodeficiency, and cancer predisposition. The archetype for such disorders is Ataxia-Telangiectasia caused by biallelic mutation in ATM, a central component of the DNA damage response. Here, we report that the ubiquitin ligase RNF168 is mutated in the RIDDLE syndrome, a recently discovered immunodeficiency and radiosensitivity disorder. We show that RNF168 is recruited to sites of DNA damage by binding to ubiquitylated histone H2A. RNF168 acts with UBC13 to amplify the RNF8-dependent histone ubiquitylation by targeting H2A-type histones and by promoting the formation of lysine 63-linked ubiquitin conjugates. These RNF168-dependent chromatin modifications orchestrate the accumulation of 53BP1 and BRCA1 to DNA lesions, and their loss is the likely cause of the cellular and developmental phenotypes associated with RIDDLE syndrome.

U2 - 10.1016/j.cell.2008.12.042

DO - 10.1016/j.cell.2008.12.042

M3 - Article

C2 - 19203578

SN - 0092-8674

VL - 136

SP - 420

EP - 434

JO - Cell

JF - Cell

IS - 3

ER -

The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage.

Abstract

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