Histone Ubiquitination by the DNA Damage Response Is Required for Efficient DNA Replication in Unperturbed S Phase
Chromatin ubiquitination by the ubiquitin ligase RNF168 is critical to regulate the DNA damage response (DDR). DDR deficiencies lead to cancer-prone syndromes, but whether this reflects DNA repair defects is still elusive. We identified key factors of the RNF168 pathway as essential mediators of eff...
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| Vydáno v: | Molecular cell Ročník 71; číslo 6; s. 897 |
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| Hlavní autoři: | , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
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United States
20.09.2018
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| ISSN: | 1097-4164, 1097-4164 |
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| Abstract | Chromatin ubiquitination by the ubiquitin ligase RNF168 is critical to regulate the DNA damage response (DDR). DDR deficiencies lead to cancer-prone syndromes, but whether this reflects DNA repair defects is still elusive. We identified key factors of the RNF168 pathway as essential mediators of efficient DNA replication in unperturbed S phase. We found that loss of RNF168 leads to reduced replication fork progression and to reversed fork accumulation, particularly evident at repetitive sequences stalling replication. Slow fork progression depends on MRE11-dependent degradation of reversed forks, implicating RNF168 in reversed fork protection and restart. Consistent with regular nucleosomal organization of reversed forks, the replication function of RNF168 requires H2A ubiquitination. As this novel function is shared with the key DDR players ATM, γH2A.X, RNF8, and 53BP1, we propose that double-stranded ends at reversed forks engage classical DDR factors, suggesting an alternative function of this pathway in preventing genome instability and human disease. |
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| AbstractList | Chromatin ubiquitination by the ubiquitin ligase RNF168 is critical to regulate the DNA damage response (DDR). DDR deficiencies lead to cancer-prone syndromes, but whether this reflects DNA repair defects is still elusive. We identified key factors of the RNF168 pathway as essential mediators of efficient DNA replication in unperturbed S phase. We found that loss of RNF168 leads to reduced replication fork progression and to reversed fork accumulation, particularly evident at repetitive sequences stalling replication. Slow fork progression depends on MRE11-dependent degradation of reversed forks, implicating RNF168 in reversed fork protection and restart. Consistent with regular nucleosomal organization of reversed forks, the replication function of RNF168 requires H2A ubiquitination. As this novel function is shared with the key DDR players ATM, γH2A.X, RNF8, and 53BP1, we propose that double-stranded ends at reversed forks engage classical DDR factors, suggesting an alternative function of this pathway in preventing genome instability and human disease.Chromatin ubiquitination by the ubiquitin ligase RNF168 is critical to regulate the DNA damage response (DDR). DDR deficiencies lead to cancer-prone syndromes, but whether this reflects DNA repair defects is still elusive. We identified key factors of the RNF168 pathway as essential mediators of efficient DNA replication in unperturbed S phase. We found that loss of RNF168 leads to reduced replication fork progression and to reversed fork accumulation, particularly evident at repetitive sequences stalling replication. Slow fork progression depends on MRE11-dependent degradation of reversed forks, implicating RNF168 in reversed fork protection and restart. Consistent with regular nucleosomal organization of reversed forks, the replication function of RNF168 requires H2A ubiquitination. As this novel function is shared with the key DDR players ATM, γH2A.X, RNF8, and 53BP1, we propose that double-stranded ends at reversed forks engage classical DDR factors, suggesting an alternative function of this pathway in preventing genome instability and human disease. Chromatin ubiquitination by the ubiquitin ligase RNF168 is critical to regulate the DNA damage response (DDR). DDR deficiencies lead to cancer-prone syndromes, but whether this reflects DNA repair defects is still elusive. We identified key factors of the RNF168 pathway as essential mediators of efficient DNA replication in unperturbed S phase. We found that loss of RNF168 leads to reduced replication fork progression and to reversed fork accumulation, particularly evident at repetitive sequences stalling replication. Slow fork progression depends on MRE11-dependent degradation of reversed forks, implicating RNF168 in reversed fork protection and restart. Consistent with regular nucleosomal organization of reversed forks, the replication function of RNF168 requires H2A ubiquitination. As this novel function is shared with the key DDR players ATM, γH2A.X, RNF8, and 53BP1, we propose that double-stranded ends at reversed forks engage classical DDR factors, suggesting an alternative function of this pathway in preventing genome instability and human disease. |
| Author | Raso, Maria Chiara Stoy, Henriette Krietsch, Jana Freire, Raimundo Penengo, Lorenza Ursich, Sebastian Lopes, Massimo Berti, Matteo Walser, Franziska Schmid, Fabian Schmid, Jonas Andreas Zwicky, Katharina |
| Author_xml | – sequence: 1 givenname: Jonas Andreas surname: Schmid fullname: Schmid, Jonas Andreas organization: Institute of Molecular Cancer Research, University of Zurich, Zurich 8057, Switzerland – sequence: 2 givenname: Matteo surname: Berti fullname: Berti, Matteo organization: Institute of Molecular Cancer Research, University of Zurich, Zurich 8057, Switzerland – sequence: 3 givenname: Franziska surname: Walser fullname: Walser, Franziska organization: Institute of Molecular Cancer Research, University of Zurich, Zurich 8057, Switzerland – sequence: 4 givenname: Maria Chiara surname: Raso fullname: Raso, Maria Chiara organization: Institute of Molecular Cancer Research, University of Zurich, Zurich 8057, Switzerland – sequence: 5 givenname: Fabian surname: Schmid fullname: Schmid, Fabian organization: Institute of Molecular Cancer Research, University of Zurich, Zurich 8057, Switzerland – sequence: 6 givenname: Jana surname: Krietsch fullname: Krietsch, Jana organization: Institute of Molecular Cancer Research, University of Zurich, Zurich 8057, Switzerland – sequence: 7 givenname: Henriette surname: Stoy fullname: Stoy, Henriette organization: Institute of Molecular Cancer Research, University of Zurich, Zurich 8057, Switzerland – sequence: 8 givenname: Katharina surname: Zwicky fullname: Zwicky, Katharina organization: Institute of Molecular Cancer Research, University of Zurich, Zurich 8057, Switzerland – sequence: 9 givenname: Sebastian surname: Ursich fullname: Ursich, Sebastian organization: Institute of Molecular Cancer Research, University of Zurich, Zurich 8057, Switzerland – sequence: 10 givenname: Raimundo surname: Freire fullname: Freire, Raimundo organization: Unidad de Investigación, Hospital Universitario de Canarias, Instituto de Tecnologías Biomédicas, Ofra s/n, La Cuesta, La Laguna, Tenerife 38320, Spain – sequence: 11 givenname: Massimo surname: Lopes fullname: Lopes, Massimo email: lopes@imcr.uzh.ch organization: Institute of Molecular Cancer Research, University of Zurich, Zurich 8057, Switzerland. Electronic address: lopes@imcr.uzh.ch – sequence: 12 givenname: Lorenza surname: Penengo fullname: Penengo, Lorenza email: penengo@imcr.uzh.ch organization: Institute of Molecular Cancer Research, University of Zurich, Zurich 8057, Switzerland. Electronic address: penengo@imcr.uzh.ch |
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| Keywords | RNF168 genome stability fork reversal 53BP1 RIDDLE syndrome RNF8 ataxia telangiectasia ATM H2AK15Ub chromatin ubiquitination |
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