A role for Mus81 in the repair of chromium-induced DNA damage

Tamblyn, Laura; Li, Erica; Sarras, Haya; Srikanth, Prarthana; Hande, M. Prakash; McPherson, J. Peter

doi:10.1016/j.mrfmmm.2008.10.013

Cited by 16 publications

(16 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…34 To study whether Mus81 sumoylation had any effect on chromium responses, we transfected HEK293T cells with a plasmid expressing WT His 6 -Mus81 or His 6 -Mus81-5R followed by treatment with Cr(VI) for various times. Immunoblotting revealed that cells transfected with His 6 -Mus81-5R contained a lower level of g-H2AX than those transfected with the WT counterpart (Fig.…”

Section: Compromised Dna Damage Response In Cells Expressing Mus81-5rmentioning

confidence: 99%

Arsenic-induced sumoylation of Mus81 is involved in regulating genomic stability

Yang

et al. 2017

Cell Cycle

View full text Add to dashboard Cite

Chronic environmental exposure to metal toxicants such as chromium and arsenic is closely related to the development of several types of common cancers. Genetic and epigenetic studies in the past decade reveal that post-translational modifications of histones play a role in metal carcinogenesis. However, exact molecular mechanisms of metal carcinogenesis remain to be elucidated. In this study we found that As 2 O 3 , an environmental metal toxicant, upregulated overall modifications of many cellular proteins by SUMO2/3. Sumoylated proteins from arsenic-treated cells constitutively expressing His 6 -SUMO2 were pulled down by Ni-IDA resin under denaturing conditions. Mass spectrometric analysis revealed over 100 proteins that were potentially modified by sumoylation. Mus81, a DNA endonuclease involved in homologous recombination repair, was among the identified proteins whose sumoylation was increased after treatment with As 2 O 3. We further showed that K10 and K524 were 2 lysine residues essential for Mus81 sumoylation. Moreover, we demonstrated that Mus81 sumoylation is important for normal mitotic chromosome congression and that cells expressing SUMO-resistant Mus81 mutants displayed compromised DNA damage responses after exposure to metal toxins such as Cr(VI) and arsenic.

show abstract

Section: Compromised Dna Damage Response In Cells Expressing Mus81-5rmentioning

confidence: 99%

Arsenic-induced sumoylation of Mus81 is involved in regulating genomic stability

Yang

et al. 2017

Cell Cycle

View full text Add to dashboard Cite

show abstract

“…Studies from our laboratory and others, have shown the significance of respective DNA repair mechanisms paradoxically in the protection against, and promotion of Cr(VI)-induced mutagenesis. These data revealed the importance of DNA double strand break repair by homologous recombination in the promotion of cell survival following Cr(VI) exposure in yeast [78]; the role of Mus81, an enzyme involved in replication fork repair, in the repair of replication-associated Cr(VI)-induced DNA damage [79]; and the protection of cells from Cr(VI)-induced DNA damage and mutagenesis by BER and NER [77,80,81]. Interestingly, recent work has also shown that both a proficient NER-dependent mechanism and DNA polymerase ζ-mediated translesion synthesis (TLS) may mediate Cr(VI)-induced mutagenesis [77,81].…”

Section: Mode Of Action Of Chromium Carcinogenesismentioning

confidence: 99%

Chromium genotoxicity: A double-edged sword

Nickens¹,

Patierno²,

Ceryak³

2010

Chemico-Biological Interactions

321

175

View full text Add to dashboard Cite

Certain forms of hexavalent chromium [Cr(VI)] are known respiratory carcinogens that induce a broad spectrum of DNA damage. Cr(VI)-carcinogenesis may be initiated or promoted through several mechanistic processes including, the intracellular metabolic reduction of Cr(VI) producing chromium species capable of interacting with DNA to yield genotoxic and mutagenic effects, Cr(VI)-induced inflammatory/immunological responses, and alteration of survival signaling pathways. Cr(VI) enters the cell through nonspecific anion channels, and is metabolically reduced by agents including ascorbate, glutathione, and cysteine to Cr(V), Cr(IV), and Cr(III). Cr(III) has a weak membrane permeability capacity and is unable to cross the cell membrane, thereby trapping it within the cell where it can bind to DNA and produce genetic damage leading to genomic instability. Structural genetic lesions produced by the intracellular reduction of Cr(VI) include DNA adducts, DNA strand breaks, DNA-protein crosslinks, oxidized bases, abasic sites, and DNA inter-and intrastrand crosslinks. The damage induced by Cr(VI) can lead to dysfunctional DNA replication and transcription, aberrant cell cycle checkpoints, dysregulated DNA repair mechanisms, microsatelite instability, inflammatory responses, and the disruption of key regulatory gene networks responsible for the balance of cell survival and cell death, which may all play an important role in Cr(VI) carcinogenesis. Several lines of evidence have indicated that neoplastic progression is a result of consecutive genetic/epigenetic changes that provide cellular survival advantages, and ultimately lead to the conversion of normal human cells to malignant cancer cells. This review is based on studies that provide a glimpse into Cr(VI) carcinogenicity via mechanisms including Cr(VI)-induced death-resistance, the involvement of DNA repair mechanisms in survival after chromium exposure, and the activation of survival signaling cascades in response to Cr(VI) genotoxicity.

show abstract

“…Immortalization of embryonic fibroblasts with Simian virus large T antigen, clonogenic assays, cell-cycle analysis, γH2AX staining by flow cytometry and metaphase analysis were performed as previously described (32). For micronuclei enumeration, at least 200 cells/genotype were scored in triplicate.…”

Section: Methodsmentioning

confidence: 99%

Fanconi anemia signaling and Mus81 cooperate to safeguard development and crosslink repair

Larin

Gallo

Tamblyn

et al. 2014

Nucleic Acids Research

Self Cite

View full text Add to dashboard Cite

Individuals with Fanconi anemia (FA) are susceptible to bone marrow failure, congenital abnormalities, cancer predisposition and exhibit defective DNA crosslink repair. The relationship of this repair defect to disease traits remains unclear, given that crosslink sensitivity is recapitulated in FA mouse models without most of the other disease-related features. Mice deficient in Mus81 are also defective in crosslink repair, yet MUS81 mutations have not been linked to FA. Using mice deficient in both Mus81 and the FA pathway protein FancC, we show both proteins cooperate in parallel pathways, as concomitant loss of FancC and Mus81 triggered cell-type-specific proliferation arrest, apoptosis and DNA damage accumulation in utero. Mice deficient in both FancC and Mus81 that survived to birth exhibited growth defects and an increased incidence of congenital abnormalities. This cooperativity of FancC and Mus81 in developmental outcome was also mirrored in response to crosslink damage and chromosomal integrity. Thus, our findings reveal that both pathways safeguard against DNA damage from exceeding a critical threshold that triggers proliferation arrest and apoptosis, leading to compromised in utero development.

show abstract

A role for Mus81 in the repair of chromium-induced DNA damage

Cited by 16 publications

References 74 publications

Arsenic-induced sumoylation of Mus81 is involved in regulating genomic stability

Arsenic-induced sumoylation of Mus81 is involved in regulating genomic stability

Chromium genotoxicity: A double-edged sword

Fanconi anemia signaling and Mus81 cooperate to safeguard development and crosslink repair

Contact Info

Product

Resources

About