RNF111-Dependent Neddylation Activates DNA Damage-Induced Ubiquitination

Ma, Teng; Chen, Yibin; Zhang, Feng; Yang, Chao; Wang, Shaomeng; Yu, Xiaochun

doi:10.1016/j.molcel.2013.01.006

Cited by 109 publications

(137 citation statements)

References 60 publications

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“…Instead, the ubiquitinated targets act as recruitment platforms for downstream factors, which will be discussed in detail below. RNF168 recruitment is partially dependent on RNF111 and UBE2M, which are E3 and E2 enzymes, respectively, that conjugate the ubiquitin-like protein NEDD8 to a cluster of lysine residues on the N terminus of histone H4 (32). RNF168 physically interacts with "polyneddylated" H4, which is thought to be crucial for its DSB recruitment (32).…”

Section: Upstream Action Of Rnf8 and Rnf168 Ubiquitin Ligasesmentioning

confidence: 99%

53BP1, BRCA1, and the Choice between Recombination and End Joining at DNA Double-Strand Breaks

Daley

Sung

2014

Molecular and Cellular Biology

242

234

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When DNA double-strand breaks occur, the cell cycle stage has a major influence on the choice of the repair pathway employed. Specifically, nonhomologous end joining is the predominant mechanism used in the G 1 phase of the cell cycle, while homologous recombination becomes fully activated in S phase. Studies over the past 2 decades have revealed that the aberrant joining of replication-associated breaks leads to catastrophic genome rearrangements, revealing an important role of DNA break repair pathway choice in the preservation of genome integrity. 53BP1, first identified as a DNA damage checkpoint protein, and BRCA1, a well-known breast cancer tumor suppressor, are at the center of this choice. Research on how these proteins function at the DNA break site has advanced rapidly in the recent past. Here, we review what is known regarding how the repair pathway choice is made, including the mechanisms that govern the recruitment of each critical factor, and how the cell transitions from end joining in G 1 to homologous recombination in S/G 2 .

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Section: Upstream Action Of Rnf8 and Rnf168 Ubiquitin Ligasesmentioning

confidence: 99%

53BP1, BRCA1, and the Choice between Recombination and End Joining at DNA Double-Strand Breaks

Daley

Sung

2014

Molecular and Cellular Biology

242

234

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“…At first, the ubiquitin-like protein NEDD8 accumulates at DNA damage sites in an E3 ligase RNF111-dependent manner, and H4 is polyneddylated at the N-terminal lysine residues. H4 neddylation can be recognized by RNF168, and loss of H4 neddylation impairs the localization of RNF168 and its downstream functional partners, such as 53BP1 and BRCA1, thus affecting the process of DNA repair (Ma et al, 2013). In addition, the histone variant H2A.Z, and its SUMO modification, is required for DNA resection, single DSB-induced checkpoint activation, and DSB anchoring to the nuclear periphery (Kalocsay et al, 2009).…”

Section: Othersmentioning

confidence: 99%

Histone modifications in DNA damage response

Cao

Shen

Zhu

2016

Sci. China Life Sci.

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DNA damage is a relatively common event in eukaryotic cell and may lead to genetic mutation and even cancer. DNA damage induces cellular responses that enable the cell either to repair the damaged DNA or cope with the damage in an appropriate way. Histone proteins are also the fundamental building blocks of eukaryotic chromatin besides DNA, and many types of post-translational modifications often occur on tails of histones. Although the function of these modifications has remained elusive, there is ever-growing studies suggest that histone modifications play vital roles in several chromatin-based processes, such as DNA damage response. In this review, we will discuss the main histone modifications, and their functions in DNA damage response.DNA damage response, histone modifications, chromatin, DNA repair Citation:

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“…SUMO and NEDD8 are also involved in the DNA damage response (Guzzo et al, 2012;Ma et al, 2013). H4 is strongly neddylated at the N-terminal tail by the E3 ligase RNF111 (Ma et al, 2013). Here, we report that neddylation of H2A is mediated by RNF168, which competes with ubiquitylation of H2A.…”

Section: Introductionmentioning

confidence: 75%

“…These data indicate that H2A, H3 and H4 are targets of NEDD8 on the chromatin. Recently, the neddylation of H4 in response to DNA damage has been reported (Ma et al, 2013), and owing to the important function of H2A modification in DNA damage response, we thus focused our work on H2A to elucidate the mechanism of H2A neddylation and its function in VP16-induced DNA damage, and to also understand the correlation with H2A ubiquitylation. Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Histone 2A (H2A), and its variant H2AX, are modified by K63-linked polyubiquitin chains via multiple E3 ligases, including RING2 (also known as RNF2), RNF8 and RNF168 (Fang et al, 2004;Gatti et al, 2012;Huen et al, 2007;Mailand et al, 2007;Mattiroli et al, 2012;Oestergaard et al, 2012;Pinato et al, 2009;Plans et al, 2008), which facilitates the recruitment of DNA damage repair proteins, such as RAP80 and BRCA1. SUMO and NEDD8 are also involved in the DNA damage response (Guzzo et al, 2012;Ma et al, 2013). H4 is strongly neddylated at the N-terminal tail by the E3 ligase RNF111 (Ma et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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RNF168-mediated H2A neddylation antagonizes its ubiquitination and regulates DNA damage repair

Guan

Huang

et al. 2014

Journal of Cell Science

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BSTRACTNEDD8 is an important regulatory factor in many biological processes. However, the substrates for neddylation, and the relationship between the ubiquitin and NEDD8 pathways remain largely unknown. Here, we show that NEDD8 is covalently conjugated to histone 2A (H2A), and that neddylation of H2A antagonizes its ubiquitylation. NEDD8 suppresses ubiquitylation of H2A, and a decreased level of free NEDD8 promotes H2A ubiquitylation. Furthermore, we found that the E3 ligase RNF168 promotes both H2A ubiquitylation and neddylation. Interestingly, RNF168 is itself a substrate for NEDD8, and neddylation of RNF168 is necessary for its E3 ubiquitin activity. Inhibition of RNF168 neddylation impairs the interaction between RNF168 and its E2 enzyme Ubc13 (also known as UBE2N). Moreover, in response to DNA damage, the level of H2A neddylation decreased with an increase in the ubiquitylation of H2A, which facilitates DNA damage repair. During the later stages of damage repair, H2A neddylation increased gradually, whereas ubiquitylation decreased to basal levels. Mechanistically, NEDD8 negatively regulates the DNA damage repair process through suppression of the ubiquitylation of H2A and cH2AX, which further blocks the recruitment of the damage response protein BRCA1. Our findings elucidate the relationship of H2A ubiquitylation and neddylation, and suggest a novel modulatory approach to DNA damage repair through the neddylation pathway.

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RNF111-Dependent Neddylation Activates DNA Damage-Induced Ubiquitination

Cited by 109 publications

References 60 publications

53BP1, BRCA1, and the Choice between Recombination and End Joining at DNA Double-Strand Breaks

53BP1, BRCA1, and the Choice between Recombination and End Joining at DNA Double-Strand Breaks

Histone modifications in DNA damage response

RNF168-mediated H2A neddylation antagonizes its ubiquitination and regulates DNA damage repair

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