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Frank Sicheri - One of the best experts on this subject based on the ideXlab platform.
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53bp1 is a reader of the dna damage induced h2a lys 15 ubiquitin mark
Nature, 2013Co-Authors: Amelie Fradetturcotte, Sylvie M Noordermeer, Marella D Canny, Cristina Escribanodiaz, Alexandre Orthwein, Charles C Y Leung, Hao Huang, Marieclaude Landry, Julianne L Kitevskileblanc, Frank SicheriAbstract:53BP1 (also called TP53BP1) is a chromatin-associated factor that promotes immunoglobulin class switching and DNA double-strand-break (DSB) repair by non-homologous end joining. To accomplish its function in DNA repair, 53BP1 accumulates at DSB sites downstream of the RNF168 ubiquitin ligase. How ubiquitin recruits 53BP1 to break sites remains unknown as its relocalization involves recognition of Histone H4 Lys 20 (H4K20) methylation by its Tudor domain. Here we elucidate how vertebrate 53BP1 is recruited to the chromatin that flanks DSB sites. We show that 53BP1 recognizes mononucleosomes containing dimethylated H4K20 (H4K20me2) and H2A ubiquitinated on Lys 15 (H2AK15ub), the latter being a product of RNF168 action on chromatin. 53BP1 binds to nucleosomes minimally as a dimer using its previously characterized methyl-lysine-binding Tudor domain and a carboxy-terminal extension, termed the Ubiquitination-dependent recruitment (UDR) motif, which interacts with the epitope formed by H2AK15ub and its surrounding residues on the H2A tail. 53BP1 is therefore a bivalent Histone modification reader that recognizes a Histone ‘code’ produced by DSB signalling. This study shows that 53BP1 recruitment to sites of DNA damage involves dual recognition of H4K20me2 and H2AK15 Histone Ubiquitination; the ubiquitin mark and the surrounding epitope on H2A are read by a region of 53BP1 designated the Ubiquitination-dependent recruitment motif. The key DNA damage response protein 53BP1 acts by binding to chromatin at the site of a double-strand break. Previous studies suggested that 53BP1 acts after a Ubiquitination event promoted by RNF168, although its recruitment to breaks was thought to depend only on Histone H4K20 methylation. Daniel Durocher and colleagues now show that 53BP1 recruitment involves the recognition of both H4K20me2 and Histone H2AK15 Ubiquitination. The ubiquitin mark, and the surrounding context on Histone H2A, are read by a region of 53BP1 that the authors designate the Ubiquitination-dependent recruitment motif.
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53bp1 is a reader of the dna damage induced h2a lys 15 ubiquitin mark
Nature, 2013Co-Authors: Amelie Fradetturcotte, Sylvie M Noordermeer, Marella D Canny, Cristina Escribanodiaz, Alexandre Orthwein, Charles C Y Leung, Hao Huang, Marieclaude Landry, Julianne L Kitevskileblanc, Frank SicheriAbstract:This study shows that 53BP1 recruitment to sites of DNA damage involves dual recognition of H4K20me2 and H2AK15 Histone Ubiquitination; the ubiquitin mark and the surrounding epitope on H2A are read by a region of 53BP1 designated the Ubiquitination-dependent recruitment motif.
Amelie Fradetturcotte - One of the best experts on this subject based on the ideXlab platform.
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53bp1 is a reader of the dna damage induced h2a lys 15 ubiquitin mark
Nature, 2013Co-Authors: Amelie Fradetturcotte, Sylvie M Noordermeer, Marella D Canny, Cristina Escribanodiaz, Alexandre Orthwein, Charles C Y Leung, Hao Huang, Marieclaude Landry, Julianne L Kitevskileblanc, Frank SicheriAbstract:53BP1 (also called TP53BP1) is a chromatin-associated factor that promotes immunoglobulin class switching and DNA double-strand-break (DSB) repair by non-homologous end joining. To accomplish its function in DNA repair, 53BP1 accumulates at DSB sites downstream of the RNF168 ubiquitin ligase. How ubiquitin recruits 53BP1 to break sites remains unknown as its relocalization involves recognition of Histone H4 Lys 20 (H4K20) methylation by its Tudor domain. Here we elucidate how vertebrate 53BP1 is recruited to the chromatin that flanks DSB sites. We show that 53BP1 recognizes mononucleosomes containing dimethylated H4K20 (H4K20me2) and H2A ubiquitinated on Lys 15 (H2AK15ub), the latter being a product of RNF168 action on chromatin. 53BP1 binds to nucleosomes minimally as a dimer using its previously characterized methyl-lysine-binding Tudor domain and a carboxy-terminal extension, termed the Ubiquitination-dependent recruitment (UDR) motif, which interacts with the epitope formed by H2AK15ub and its surrounding residues on the H2A tail. 53BP1 is therefore a bivalent Histone modification reader that recognizes a Histone ‘code’ produced by DSB signalling. This study shows that 53BP1 recruitment to sites of DNA damage involves dual recognition of H4K20me2 and H2AK15 Histone Ubiquitination; the ubiquitin mark and the surrounding epitope on H2A are read by a region of 53BP1 designated the Ubiquitination-dependent recruitment motif. The key DNA damage response protein 53BP1 acts by binding to chromatin at the site of a double-strand break. Previous studies suggested that 53BP1 acts after a Ubiquitination event promoted by RNF168, although its recruitment to breaks was thought to depend only on Histone H4K20 methylation. Daniel Durocher and colleagues now show that 53BP1 recruitment involves the recognition of both H4K20me2 and Histone H2AK15 Ubiquitination. The ubiquitin mark, and the surrounding context on Histone H2A, are read by a region of 53BP1 that the authors designate the Ubiquitination-dependent recruitment motif.
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53bp1 is a reader of the dna damage induced h2a lys 15 ubiquitin mark
Nature, 2013Co-Authors: Amelie Fradetturcotte, Sylvie M Noordermeer, Marella D Canny, Cristina Escribanodiaz, Alexandre Orthwein, Charles C Y Leung, Hao Huang, Marieclaude Landry, Julianne L Kitevskileblanc, Frank SicheriAbstract:This study shows that 53BP1 recruitment to sites of DNA damage involves dual recognition of H4K20me2 and H2AK15 Histone Ubiquitination; the ubiquitin mark and the surrounding epitope on H2A are read by a region of 53BP1 designated the Ubiquitination-dependent recruitment motif.
Rodrigo A Bressan - One of the best experts on this subject based on the ideXlab platform.
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control of dna methylation and heterochromatic silencing by Histone h2b deUbiquitination
Nature, 2007Co-Authors: Vaniyambadi V Sridhar, Avnish Kapoor, Kangling Zhang, Paul M Hasegawa, Tao Zhou, Rodrigo A BressanAbstract:In Arabidopsis chromatin, Histone H2B is found to be monoubiquitinated, and the ubiquitin protease SUP32/UBP26 is implicated in deubiquitinating H2B to establish heterochromatic Histone modification patterns. Epigenetic regulation involves reversible changes in DNA methylation and/or Histone modification patterns1,2,3,4,5,6,7. Short interfering RNAs (siRNAs) can direct DNA methylation and heterochromatic Histone modifications, causing sequence-specific transcriptional gene silencing1,4,8,9. In animals and yeast, Histone H2B is known to be monoubiquitinated, and this regulates the methylation of Histone H3 (refs 10, 11). However, the relationship between Histone Ubiquitination and DNA methylation has not been investigated. Here we show that mutations in an Arabidopsis deUbiquitination enzyme, SUP32/UBP26, decrease the dimethylation on lysine 9 of H3, suppress siRNA-directed methylation of DNA and release heterochromatic silencing of transgenes as well as transposons. We found that Arabidopsis Histone H2B is monoubiquitinated at lysine 143 and that the levels of ubiquitinated H2B and trimethyl H3 at lysine 4 increase in sup32 mutant plants. SUP32/UBP26 can deubiquitinate H2B, and chromatin immunoprecipitation assays suggest an association between H2B Ubiquitination and release of silencing. These data suggest that H2B deUbiquitination by SUP32/UBP26 is required for heterochromatic Histone H3 methylation and DNA methylation.
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control of dna methylation and heterochromatic silencing by Histone h2b deUbiquitination
Nature, 2007Co-Authors: Vaniyambadi V Sridhar, Avnish Kapoor, Kangling Zhang, Paul M Hasegawa, Tao Zhou, Rodrigo A BressanAbstract:In Arabidopsis chromatin, Histone H2B is found to be monoubiquitinated, and the ubiquitin protease SUP32/UBP26 is implicated in deubiquitinating H2B to establish heterochromatic Histone modification patterns. Epigenetic regulation involves reversible changes in DNA methylation and/or Histone modification patterns1,2,3,4,5,6,7. Short interfering RNAs (siRNAs) can direct DNA methylation and heterochromatic Histone modifications, causing sequence-specific transcriptional gene silencing1,4,8,9. In animals and yeast, Histone H2B is known to be monoubiquitinated, and this regulates the methylation of Histone H3 (refs 10, 11). However, the relationship between Histone Ubiquitination and DNA methylation has not been investigated. Here we show that mutations in an Arabidopsis deUbiquitination enzyme, SUP32/UBP26, decrease the dimethylation on lysine 9 of H3, suppress siRNA-directed methylation of DNA and release heterochromatic silencing of transgenes as well as transposons. We found that Arabidopsis Histone H2B is monoubiquitinated at lysine 143 and that the levels of ubiquitinated H2B and trimethyl H3 at lysine 4 increase in sup32 mutant plants. SUP32/UBP26 can deubiquitinate H2B, and chromatin immunoprecipitation assays suggest an association between H2B Ubiquitination and release of silencing. These data suggest that H2B deUbiquitination by SUP32/UBP26 is required for heterochromatic Histone H3 methylation and DNA methylation.
Weiguo Zhu - One of the best experts on this subject based on the ideXlab platform.
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autophagy regulates dna repair by modulating Histone Ubiquitination
Molecular and Cellular Oncology, 2016Co-Authors: Yanan Wang, Weiguo Zhu, Ying ZhaoAbstract:Autophagy is an intracellular degradation system that delivers cytoplasmic constituents to the lysosome. Here, we report that the autophagy receptor and substrate p62/SQSTM1 inhibits DNA double-strand break -induced Histone and chromatin Ubiquitination, which has a critical role in attracting key repair factors to the break sites.
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autophagy regulates chromatin Ubiquitination in dna damage response through elimination of sqstm1 p62
Molecular Cell, 2016Co-Authors: Yanan Wang, Nan Zhang, Luyao Zhang, Lina Wang, Jiadong Wang, Hongquan Zhang, Weiguo Zhu, Ying ZhaoAbstract:Autophagy is an intracellular degradation system that delivers cytoplasmic constituents to the lysosome, and loss of autophagy has been linked to increased genome instability. Here, we report that loss of autophagy is coupled to reduced Histone H2A Ubiquitination after DNA damage. p62/SQSTM1, which accumulates in autophagy-defective cells, directly binds to and inhibits nuclear RNF168, an E3 ligase essential for Histone H2A Ubiquitination and DNA damage responses. As a result, DNA repair proteins such as BRCA1, RAP80, and Rad51 cannot be recruited to the sites of DNA double-strand breaks (DSBs), which impairs DSB repair. Moreover, nuclear-localized p62 increased the sensitivity of tumor cells to radiation both in vitro and in vivo, and this required its interaction with RNF168. Our findings indicate that autophagy-deficiency-induced p62 accumulation results in inhibition of Histone Ubiquitination and highlight the complex relationship between autophagy and the DNA damage response.
Junjie Chen - One of the best experts on this subject based on the ideXlab platform.
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Histone Ubiquitination associates with BRCA1-dependent DNA damage response. Molecular and cellular biology. 2009; 29:849–860. [PubMed: 19015238
2014Co-Authors: Michael S Y Huen, Yali Dou, Mats Ljungman, Junjie ChenAbstract:Histone Ubiquitination participates in multiple cellular processes including the DNA damage response. However, the molecular mechanisms involved are not clear. Here, we have identified that RAP80/UIMC1 (Ubiquitin Interaction Motif Containing 1), a functional partner of BRCA1, recognizes ubiquitinated Histone H2A and H2B. The interaction between RAP80 and ubiquitinated Histone H2A and H2B is increased following DNA damage. Since RAP80 facilitates BRCA1’s translocation to DNA damage sites, our results indicate that ubiquitinated Histone H2A and H2B could be upstream partners of BRCA1-RAP80 complex in the DNA damage response. Moreover, we have found that RNF8 (Ring Finger Protein 8), an E3 ubiquitin ligase, regulates both Histone H2A and H2B Ubiquitination. In RNF8-deficient MEFs, both Histone H2A and H2B Ubiquitination are dramatically reduced, which abolishes the DNA damage-induced BRCA1 and RAP80 accumulation at damage lesions on the chromatin. Taken together, our results suggest that ubiquitinated Histone H2A and H2B may recruit BRCA1 complex to DNA damage lesions on the chromatin. 2 CC
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Histone Ubiquitination associates with brca1 dependent dna damage response
Molecular and Cellular Biology, 2009Co-Authors: Michael S Y Huen, Yali Dou, Mats Ljungman, Junjie ChenAbstract:Histone Ubiquitination participates in multiple cellular processes, including the DNA damage response. However, the molecular mechanisms involved are not clear. Here, we have identified that RAP80/UIMC1 (ubiquitin interaction motif containing 1), a functional partner of BRCA1, recognizes ubiquitinated Histones H2A and H2B. The interaction between RAP80 and ubiquitinated Histones H2A and H2B is increased following DNA damage. Since RAP80 facilitates BRCA1’s translocation to DNA damage sites, our results indicate that ubiquitinated Histones H2A and H2B could be upstream partners of the BRCA1/RAP80 complex in the DNA damage response. Moreover, we have found that RNF8 (ring finger protein 8), an E3 ubiquitin ligase, regulates Ubiquitination of both Histones H2A and H2B. In RNF8-deficient mouse embryo fibroblasts, Ubiquitination of both Histones H2A and H2B is dramatically reduced, which abolishes the DNA damage-induced BRCA1 and RAP80 accumulation at damage lesions on the chromatin. Taken together, our results suggest that ubiquitinated Histones H2A and H2B may recruit the BRCA1 complex to DNA damage lesions on the chromatin.