The Rix1 (Ipi1p-2p-3p) complex is a critical determinant of DNA replication licensing independent of their roles in ribosome biogenesis

Lin, Hui-Kuan; Wu, Rentian; Yu, Zujiang; Zhai, Yuanliang; Yang, Xiaoxia; Chan, Tsz Choi; Yeung, Jeffrey T.F.; Kan, Junsuo; Liang, Chun

doi:10.4161/cc.19709

Cited by 17 publications

(91 citation statements)

References 59 publications

(86 reference statements)

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“…Similar coordination between DNA replication and rDNA biogenesis by DNA replication initiators has been reported in yeast where the nucleolar-complex-associated protein Noc3p (Zhang et al, 2002) and Ipi3p proteins (Huo et al, 2012) play dual rules in DNA replication and ribosome biogenesis. Noc3p, a nucleolar protein that is required for pre-ribosome transport, interacts with MCM and Orc2, and is essential for Cdc6 and MCM chromatin association and DNA replication initiation (Zhang et al, 2002).…”

Section: Discussionmentioning

confidence: 78%

“…Noc3p, a nucleolar protein that is required for pre-ribosome transport, interacts with MCM and Orc2, and is essential for Cdc6 and MCM chromatin association and DNA replication initiation (Zhang et al, 2002). The Rix1 complex (Ipi1p-Ipi2p-Ipi3p), which plays a role in ribosome biogenesis, has also been identified as a prereplication complex component (Huo et al, 2012). Combining these previous reports and the present work, it is an intriguing hypothesis that DNA replication initiators (Cdc6 for rDNA transcription, Ipi1-3 in pre-rRNA processing and Noc3 for the pre-ribosome, and perhaps others) form a network to coordinate DNA replication and ribosome biogenesis.…”

Section: Discussionmentioning

confidence: 99%

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DNA replication initiator Cdc6 also regulates ribosomal DNA transcription initiation

Huang

Wang

et al. 2016

Journal of Cell Science

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RNA-polymerase-I-dependent ribosomal DNA (rDNA) transcription is fundamental to rRNA processing, ribosome assembly and protein synthesis. However, how this process is initiated during the cell cycle is not fully understood. By performing a proteomic analysis of transcription factors that bind RNA polymerase I during rDNA transcription initiation, we identified that the DNA replication initiator Cdc6 interacts with RNA polymerase I and its co-factors, and promotes rDNA transcription in G1 phase in an ATPaseactivity-dependent manner. We further showed that Cdc6 is targeted to the nucleolus during late mitosis and G1 phase in a manner that is dependent on B23 (also known as nucleophosmin, NPM1), and preferentially binds to the rDNA promoter through its ATP-binding domain. Overexpression of Cdc6 increases rDNA transcription, whereas knockdown of Cdc6 results in a decreased association of both RNA polymerase I and the RNA polymerase I transcription factor RRN3 with rDNA, and a reduction of rDNA transcription. Furthermore, depletion of Cdc6 impairs the interaction between RRN3 and RNA polymerase I. Taken together, our data demonstrate that Cdc6 also serves as a regulator of rDNA transcription initiation, and indicate a mechanism by which initiation of rDNA transcription and DNA replication can be coordinated in cells.

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

DNA replication initiator Cdc6 also regulates ribosomal DNA transcription initiation

Huang

Wang

et al. 2016

Journal of Cell Science

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“…Given a little known role of the normally monoubiquitinated FANCD2 in DNA replication, we asked whether FANCD2 has any effects on the very beginning of the replication process: the normal replication origin firing that pre-requires an adequate number of replication origins assembled ready with MCM complexes [10, 24-27]. First, we asked whether FANCD2 is localized at origins of DNA replication, noting that monoubiquitinated FANCD2 interacts with chromatin [28].…”

Section: Resultsmentioning

confidence: 99%

Basal level of FANCD2 monoubiquitination is required for the maintenance of a sufficient number of licensed-replication origins to fire at a normal rate

et al. 2014

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Normal DNA replication starts following the stepwise recruitment of replication initiators to assemble Mini-chromosome Maintenance (MCM) 2-7 protein complexes at an adequate amount of DNA replication origins. Under normal conditions, the monoubiquitination of Fanconi Anemia (FA) group D2 protein (FANCD2) occurs in each S-phase of cell cycle, which is the basal level of FANCD2 monoubiquitination. However, little is known regarding the roles of this basal level of monoubiquitinated FANCD2. Here we show that monoubiquitinated FANCD2 in each S-phase of normal cell cycle is essential for replication origins to fire at a normal rate. We found that the basal level of the monoubiquitinated FANCD2 can interact with replication origins as well as mini-chromosome maintenance protein 3 (MCM3) in an S-phase specific manner to secure an enough number of the licensed-origins to fire. Non-monoubiquitinated FANCD2 or mutant MCM3 lacking AA 477-480 responsible for interacting with FANCD2 can lead to an insufficient amount of licensed origins to fire and, thereby, enlarged intervals between the fired origins. Our results demonstrate that the monoubiquitinated FANCD2 in each S-phase of normal cell cycle is required to maintain an enough number of licensed origins to initiate the normal DNA replication. This finding is the first to provide insights into how FANCD2 functions under normal condition of cell cycle to maintain genome stability, as well as resulting implications in the strategic improvement for the fight against human cancer.

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“…Because most of the replication proteins associate with chromatin from G1 to S phase (30), we asked whether the association of Kdm4d and replication proteins is regulated during the cell cycle. To test this possibility, we examined the interaction between Kdm4d and replication proteins in cells synchronized at different phases of the cell cycle.…”

Section: Resultsmentioning

confidence: 99%

“…Co-immunoprecipitation assay was performed as described previously (30), in which cells were lysed using the buffer (50 mM HEPES–KOH, pH 7.4, 200 mM NaCl, 0.5% NP40, 10% glycerol, 1 mM ethylenediaminetetraacetic acid (EDTA) and proteinase inhibitors) and homogenizated for 30 times by dounce homogenizer. After clarification by centrifugation, 7.5 μl ethidium- bromide (10 mg/ml) was added to the lysates.…”

Section: Methodsmentioning

confidence: 99%

H3K9me3 demethylase Kdm4d facilitates the formation of pre-initiative complex and regulates DNA replication

Wang

Zhang

et al. 2016

Nucleic Acids Res

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DNA replication is tightly regulated to occur once and only once per cell cycle. How chromatin, the physiological substrate of DNA replication machinery, regulates DNA replication remains largely unknown. Here we show that histone H3 lysine 9 demethylase Kdm4d regulates DNA replication in eukaryotic cells. Depletion of Kdm4d results in defects in DNA replication, which can be rescued by the expression of H3K9M, a histone H3 mutant transgene that reverses the effect of Kdm4d on H3K9 methylation. Kdm4d interacts with replication proteins, and its recruitment to DNA replication origins depends on the two pre-replicative complex components (origin recognition complex [ORC] and minichromosome maintenance [MCM] complex). Depletion of Kdm4d impairs the recruitment of Cdc45, proliferating cell nuclear antigen (PCNA), and polymerase δ, but not ORC and MCM proteins. These results demonstrate a novel mechanism by which Kdm4d regulates DNA replication by reducing the H3K9me3 level to facilitate formation of pre-initiative complex.

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The Rix1 (Ipi1p-2p-3p) complex is a critical determinant of DNA replication licensing independent of their roles in ribosome biogenesis

Cited by 17 publications

References 59 publications

DNA replication initiator Cdc6 also regulates ribosomal DNA transcription initiation

DNA replication initiator Cdc6 also regulates ribosomal DNA transcription initiation

Basal level of FANCD2 monoubiquitination is required for the maintenance of a sufficient number of licensed-replication origins to fire at a normal rate

H3K9me3 demethylase Kdm4d facilitates the formation of pre-initiative complex and regulates DNA replication

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