The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage
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The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage. / Stewart, Grant S.; Panier, Stephanie; Townsend, Kelly; Al-Hakim, Abdallah K.; Kolas, Nadine K.; Miller, Edward S.; Nakada, Shinichiro; Ylanko, Jarkko; Olivarius, Signe; Mendez, Megan; Oldreive, Ceri; Wildenhain, Jan; Tagliaferro, Andrea; Pelletier, Laurence; Taubenheim, Nadine; Durandy, Anne; Byrd, Philip J.; Stankovic, Tatjana; Taylor, A. Malcolm R.; Durocher, Daniel.
In: Cell, Vol. 136, No. 3, 2009, p. 420-434.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage
AU - Stewart, Grant S.
AU - Panier, Stephanie
AU - Townsend, Kelly
AU - Al-Hakim, Abdallah K.
AU - Kolas, Nadine K.
AU - Miller, Edward S.
AU - Nakada, Shinichiro
AU - Ylanko, Jarkko
AU - Olivarius, Signe
AU - Mendez, Megan
AU - Oldreive, Ceri
AU - Wildenhain, Jan
AU - Tagliaferro, Andrea
AU - Pelletier, Laurence
AU - Taubenheim, Nadine
AU - Durandy, Anne
AU - Byrd, Philip J.
AU - Stankovic, Tatjana
AU - Taylor, A. Malcolm R.
AU - Durocher, Daniel
N1 - Paper id:: 19203578
PY - 2009
Y1 - 2009
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.
KW - Faculty of Science
KW - DNA
KW - signalering
KW - DNA
KW - signaling
U2 - 10.1016/j.cell.2008.12.042
DO - 10.1016/j.cell.2008.12.042
M3 - Journal article
C2 - 19203578
VL - 136
SP - 420
EP - 434
JO - Cell
JF - Cell
SN - 0092-8674
IS - 3
ER -
ID: 17901596