Cross-species Functionome analysis identifies proteins associated with DNA repair, translation and aerobic respiration as conserved modulators of UV-toxicity

Rooney, John P.; Patil, Ashish; Joseph, Fraulin; Endres, Lauren; Begley, Ulrike; Zappalà, Maria; Cunningham, Richard P.; Begley, Thomas J.

doi:10.1016/j.ygeno.2010.12.005

Cited by 6 publications

(6 citation statements)

References 50 publications

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“…The domain architecture of Orf1 belongs to the first group, of which 48 sequences were annotated as putative uncharacterized YcaQ protein. In E. coli strain K12, the YcaQ was identified as one of UVC-toxicity modulating proteins with an unknown role ( 26 ). It is worth noting that 31 of these putative YcaQ proteins are from common pathogens in Enterobacteriaceae and 3 come from antibiotic producers.…”

Section: Resultsmentioning

confidence: 99%

Characterization of a novel DNA glycosylase fromS. sahachiroiinvolved in the reduction and repair of azinomycin B induced DNA damage

Wang

Xiao

et al. 2015

Nucleic Acids Res

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Azinomycin B is a hybrid polyketide/nonribosomal peptide natural product and possesses antitumor activity by interacting covalently with duplex DNA and inducing interstrand crosslinks. In the biosynthetic study of azinomycin B, a gene (orf1) adjacent to the azinomycin B gene cluster was found to be essential for the survival of the producer, Streptomyces sahachiroi ATCC33158. Sequence analyses revealed that Orf1 belongs to the HTH_42 superfamily of conserved bacterial proteins which are widely distributed in pathogenic and antibiotic-producing bacteria with unknown functions. The protein exhibits a protective effect against azinomycin B when heterologously expressed in azinomycin-sensitive strains. EMSA assays showed its sequence nonspecific binding to DNA and structure-specific binding to azinomycin B-adducted sites, and ChIP assays revealed extensive association of Orf1 with chromatin in vivo. Interestingly, Orf1 not only protects target sites by protein–DNA interaction but is also capable of repairing azinomycin B-mediated DNA cross-linking. It possesses the DNA glycosylase-like activity and specifically repairs DNA damage induced by azinomycin B through removal of both adducted nitrogenous bases in the cross-link. This bifunctional protein massively binds to genomic DNA to reduce drug attack risk as a novel DNA binding protein and triggers the base excision repair system as a novel DNA glycosylase.

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Section: Resultsmentioning

confidence: 99%

Characterization of a novel DNA glycosylase fromS. sahachiroiinvolved in the reduction and repair of azinomycin B induced DNA damage

Wang

Xiao

et al. 2015

Nucleic Acids Res

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“…Our cross species analysis was performed similar to a reported analysis (19). Briefly, to determine if the same gene ontology biological processes were enriched in the alkylation sensitive hit lists from all three organisms, representing X number of genes, we aligned the GO-terms from each organism.…”

Section: Methodsmentioning

confidence: 97%

“…Many similar biological processes were also highly enriched in previous DNA alkylation screens performed in S. cerevisiae and E. coli (17, 18). We combined the selected hits from all three species and performed a functionome analysis to identify significantly enriched biological processes conserved across all three organisms (19). This allowed us to create a cross-species network representing the shared alkylation response from bacteria, yeast and humans and demonstrates an Alkylation Functionome that includes many novel proteins not previously thought to impact alkylation resistance.…”

Section: Introductionmentioning

confidence: 99%

Alkylation Sensitivity Screens Reveal a Conserved Cross-species Functionome

Svilar

Dyavaiah

Brown

et al. 2012

Molecular Cancer Research

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To identify genes that contribute to chemotherapy resistance in glioblastoma, we conducted a synthetic lethal screen in a chemotherapy-resistant glioblastoma derived cell line with the clinical alkylator temozolomide (TMZ) and an siRNA library tailored towards “druggable” targets. Select DNA repair genes in the screen were validated independently, confirming the DNA glycosylases UNG and MYH as well as MPG to be involved in the response to high dose TMZ. The involvement of UNG and MYH is likely the result of a TMZ-induced burst of reactive oxygen species. We then compared the human TMZ sensitizing genes identified in our screen with those previously identified from alkylator screens conducted in E. coli and S. cerevisiae. The conserved biological processes across all three species composes an Alkylation Functionome that includes many novel proteins not previously thought to impact alkylator resistance. This high-throughput screen, validation and cross-species analysis was then followed by a mechanistic analysis of two essential nodes: base excision repair (BER) DNA glycosylases (UNG, human and mag1, S. cerevisiae) and protein modification systems, including UBE3B and ICMT in human cells or pby1, lip22, stp22 and aim22 in S. cerevisiae. The conserved processes of BER and protein modification were dual targeted and yielded additive sensitization to alkylators in S. cerevisiae. In contrast, dual targeting of BER and protein modification genes in human cells did not increase sensitivity, suggesting an epistatic relationship. Importantly, these studies provide potential new targets to overcome alkylating agent resistance.

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“…Correction of solar damage, primarily CPDs and 6‐4 PPs, can be achieved by two main mechanisms: photoreactivation (PR) and nucleotide excision repair (NER). The nearly universal presence of these metabolic pathways in cells indicates a very early requirement for DNA repair in the evolutionary history of life and this conclusion is supported by observed homologies in gene and protein sequences .…”

Section: Dna Damage and Repairmentioning

confidence: 77%

Beyond Xeroderma Pigmentosum: DNA Damage and Repair in an Ecological Context. A Tribute to James E. Cleaver

Karentz

2014

Photochem & Photobiology

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The ability to repair DNA is a ubiquitous characteristic of life on Earth and all organisms possess similar mechanisms for dealing with DNA damage, an indication of a very early evolutionary origin for repair processes. James E. Cleaver's career (initiated in the early 1960s) has been devoted to the study of mammalian ultraviolet radiation (UVR) photobiology, specifically the molecular genetics of xeroderma pigmentosum and other human diseases caused by defects in DNA damage recognition and repair. This work by Jim and others has influenced the study of DNA damage and repair in a variety of taxa. Today, the field of DNA repair is enhancing our understanding of not only how to treat and prevent human disease, but is providing insights on the evolutionary history of life on Earth and how natural populations are coping with UVR-induced DNA damage from anthropogenic changes in the environment such as ozone depletion.

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Cross-species Functionome analysis identifies proteins associated with DNA repair, translation and aerobic respiration as conserved modulators of UV-toxicity

Cited by 6 publications

References 50 publications

Characterization of a novel DNA glycosylase fromS. sahachiroiinvolved in the reduction and repair of azinomycin B induced DNA damage

Characterization of a novel DNA glycosylase fromS. sahachiroiinvolved in the reduction and repair of azinomycin B induced DNA damage

Alkylation Sensitivity Screens Reveal a Conserved Cross-species Functionome

Beyond Xeroderma Pigmentosum: DNA Damage and Repair in an Ecological Context. A Tribute to James E. Cleaver

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