Formin-mediated epigenetic maintenance of centromere identity

Liu, Chenshu; Mao, Yinghui

doi:10.1080/21541248.2016.1215658

Cited by 6 publications

(4 citation statements)

References 39 publications

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“…XPA roles in cell cycle progression were observed by the downregulation of the XPA-binding protein 2 (XAB2) affecting the transcription of mitotic related genes, including the centrosome-associated gene E (CENP-E) (Hou et al, 2016). On the other hand, Rho pathway is related to centrosome organization through the effector mDia2 by maintaining the correct levels of CENP-A at the centrosomes (Liu and Mao, 2017), therefore highlighting a potential correlation between Rho pathway and XPA protein, even independently of NER pathway, thus contributing for the understanding of cellular responses reported here. Indeed, Rho LoF is still able to increase sensitivity of NER-deficient cells to UV radiation effects by elevating the levels of DNA fragmentation and accumulation of CPD lesions (Figures 6, 7 and Supplementary Figures 6, 7).…”

Section: Discussionmentioning

confidence: 99%

RHOAming Through the Nucleotide Excision Repair Pathway as a Mechanism of Cellular Response Against the Effects of UV Radiation

Magalhães

Silva

Osaki

et al. 2020

Front. Cell Dev. Biol.

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Typical Rho GTPases include the enzymes RhoA, Rac1, and Cdc42 that act as molecular switches to regulate essential cellular processes in eukaryotic cells such as actomyosin dynamics, cell cycle, adhesion, death and differentiation. Recently, it has been shown that different conditions modulate the activity of these enzymes, but their functions still need to be better understood. Here we examine the interplay between RhoA and the NER (Nucleotide Excision Repair) pathway in human cells exposed to UVA, UVB or UVC radiation. The results show high levels and accumulation of UV-induced DNA lesions (strand breaks and cyclobutane pyrimidine dimers, CPDs) in different cells with RhoA loss of function (LoF), either by stable overexpression of negative dominant RhoA (RhoA-N19 mutant), by inhibition with C3 toxin or by transient silencing with siRNA. Cells under RhoA LoF showed reduced levels of γH2AX, p-Chk1 (Ser345) and p-p53 (Ser15) that reflected causally in their accumulation in G1/S phases, in low survival rates and in reduced cell proliferation, also in accordance with the energy of applied UV light. Even NER-deficient cells (XPA, XPC) or DNA translesion synthesis (TLS)-deficient cells (XPV) showed substantial hypersensitivity to UV effects when previously submitted to RhoA LoF. In contrast, analyses of apoptosis, necrosis, autophagy and senescence revealed that all cells displaying normal levels of active RhoA (RhoA-GTP) are more resistant to UV-promoted cell death. This work reaffirms the role of RhoA protein signaling in protecting cells from damage caused by UV radiation and demonstrates relevant communicating mechanisms between actin cytoskeleton and genomic stability.

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Section: Discussionmentioning

confidence: 99%

RHOAming Through the Nucleotide Excision Repair Pathway as a Mechanism of Cellular Response Against the Effects of UV Radiation

Magalhães

Silva

Osaki

et al. 2020

Front. Cell Dev. Biol.

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“…These factors include the Rho GTPase MgcRacGAP, the formin protein mDia, and the RSF-1 remodeling complex, and appear to be recruited to centromeres later than Mis18 and HJURP (Fig. 1) (Izuta et al 2006; Lagana et al 2010; Liu and Mao 2016; Obuse et al 2004; Perpelescu et al 2009). …”

Section: Centromere Stabilization and Re-organizationmentioning

confidence: 99%

“…The constitutively active form of mDia2 restores CENP-A levels at the centromere resulting from MgcRacGAP downregulation, consistent with its role downstream of MgcRacGAP in this process. Interestingly, mDia2 depletion leads to prolonged HJURP association with the centromere, suggesting that the processes of HJURP recruitment and MgcRacGAP stabilization are mechanistically linked (Liu and Mao 2016). …”

Section: Centromere Stabilization and Re-organizationmentioning

confidence: 99%

Orchestrating the Specific Assembly of Centromeric Nucleosomes

Zasadzińska

Foltz

2017

Progress in Molecular and Subcellular Biology

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Centromeres are chromosomal loci that are defined epigenetically in most eukaryotes by incorporation of a centromere-specific nucleosome in which the canonical histone H3 variant is replaced by Centromere Protein A (CENP-A). Therefore, the assembly and propagation of centromeric nucleosomes are critical for maintaining centromere identify and ensuring genomic stability. Centromeres direct chromosome segregation (during mitosis and meiosis) by recruiting the constitutive centromere-associated network of proteins throughout the cell cycle that in turn recruits the kinetochore during mitosis. Assembly of centromere-specific nucleosomes in humans requires the dedicated CENP-A chaperone HJURP, and the Mis18 complex to couple the deposition of new CENP-A to the site of the pre-existing centromere, which is essential for maintaining centromere identity. Human CENP-A deposition occurs specifically in early G1, into pre-existing chromatin, and several additional chromatin-associated complexes regulate CENP-A nucleosome deposition and stability. Here we review the current knowledge on how new CENP-A nucleosomes are assembled selectively at the existing centromere in different species and how this process is controlled to ensure stable epigenetic inheritance of the centromere.

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“…The diaphanous formin (mDia) proteins are important small Rho GTPase effectors and can regulate cytoskeletal dynamics by stabilizing microtubules and nucleating filamentous actin in a linear fashion ( Chesarone et al., 2010 ). Previously we have reported that formin mDia2 is required for maintaining CENP-A levels at the centromere ( Liu and Mao, 2016 , Liu and Mao, 2017 ). Importantly, overexpressing a constitutively active form of mDia2 can rescue defective centromeric CENP-A levels caused by depleting MgcRacGAP.…”

Section: Introductionmentioning

confidence: 99%

Nuclear Actin Polymerized by mDia2 Confines Centromere Movement during CENP-A Loading

2018

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SummaryCentromeres are specialized chromosomal regions epigenetically defined by the histone H3 variant centromere protein A (CENP-A). CENP-A needs to be replenished in every cell cycle, but how new CENP-A is stably incorporated into centromeric chromatin remains unclear. We have discovered that a cytoskeletal protein, diaphanous formin mDia2, is essential for the stable incorporation of new CENP-A proteins into centromeric nucleosomes. Here we report that mDia2-mediated formation of dynamic and short nuclear actin filaments in G1 nucleus is required to maintain CENP-A levels at the centromere. Importantly, mDia2 and nuclear actin are required for constrained centromere movement during CENP-A loading, and depleting nuclear actin or MgcRacGAP, which lies upstream of mDia2, extends centromeric association of the CENP-A loading chaperone Holliday junction recognition protein (HJURP). Our findings thus suggest that nuclear actin polymerized by mDia2 contributes to the physical confinement of G1 centromeres so that HJURP-mediated CENP-A loading reactions can be productive, and centromere's epigenetic identity can be stably maintained.

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Formin-mediated epigenetic maintenance of centromere identity

Cited by 6 publications

References 39 publications

RHOAming Through the Nucleotide Excision Repair Pathway as a Mechanism of Cellular Response Against the Effects of UV Radiation

RHOAming Through the Nucleotide Excision Repair Pathway as a Mechanism of Cellular Response Against the Effects of UV Radiation

Orchestrating the Specific Assembly of Centromeric Nucleosomes

Nuclear Actin Polymerized by mDia2 Confines Centromere Movement during CENP-A Loading

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