scholarly journals Nucleophosmin modulates stability, activity, and nucleolar accumulation of base excision repair proteins

2014 ◽  
Vol 25 (10) ◽  
pp. 1641-1652 ◽  
Author(s):  
Mattia Poletto ◽  
Lisa Lirussi ◽  
David M. Wilson ◽  
Gianluca Tell
Keyword(s):  
Dna Damage Response ◽  
Base Excision Repair ◽  
Genome Stability ◽  
Excision Repair ◽  
Multifunctional Protein ◽  
Protein Levels ◽  
Exact Function ◽  
Damage Response ◽  
Base Excision ◽  
Representative Protein

Nucleophosmin (NPM1) is a multifunctional protein that controls cell growth and genome stability via a mechanism that involves nucleolar–cytoplasmic shuttling. It is clear that NPM1 also contributes to the DNA damage response, yet its exact function is poorly understood. We recently linked NPM1 expression to the functional activation of the major abasic endonuclease in mammalian base excision repair (BER), apurinic/apyrimidinic endonuclease 1 (APE1). Here we unveil a novel role for NPM1 as a modulator of the whole BER pathway by 1) controlling BER protein levels, 2) regulating total BER capacity, and 3) modulating the nucleolar localization of several BER enzymes. We find that cell treatment with the genotoxin cisplatin leads to concurrent relocalization of NPM1 and BER components from nucleoli to the nucleoplasm, and cellular experiments targeting APE1 suggest a role for the redistribution of nucleolar BER factors in determining cisplatin toxicity. Finally, based on the use of APE1 as a representative protein of the BER pathway, our data suggest a function for BER proteins in the regulation of ribogenesis.

scholarly journals Base Excision Repair AP-Endonucleases-Like Genes Modulate DNA Damage Response and Virulence of the Human Pathogen Cryptococcus neoformans

2021 ◽  
Vol 7 (2) ◽  
pp. 133
Author(s):  
Rayssa Karla de Medeiros Oliveira ◽  
Fabián Andrés Hurtado ◽  
Pedro Henrique Gomes ◽  
Luiza Lassi Puglia ◽  
Fernanda Fonsêca Ferreira ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Cryptococcus Neoformans ◽  
Dna Damage Response ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Antifungal Drugs ◽  
Host Immune System ◽  
Damage Response ◽  
Base Excision

Pathogenic microbes are exposed to a number of potential DNA-damaging stimuli during interaction with the host immune system. Microbial survival in this situation depends on a fine balance between the maintenance of DNA integrity and the adaptability provided by mutations. In this study, we investigated the association of the DNA repair response with the virulence of Cryptococcus neoformans, a basidiomycete that causes life-threatening meningoencephalitis in immunocompromised individuals. We focused on the characterization of C. neoformansAPN1 and APN2 putative genes, aiming to evaluate a possible role of the predicted Apurinic/apyrimidinic (AP) endonucleases 1 and 2 of the base excision repair (BER) pathway on C. neoformans response to stress conditions and virulence. Our results demonstrated the involvement of the putative AP-endonucleases Apn1 and Apn2 in the cellular response to DNA damage induced by alkylation and by UV radiation, in melanin production, in tolerance to drugs and in virulence of C. neoformans in vivo. We also pointed out the potential use of DNA repair inhibitor methoxy-amine in combination with conventional antifungal drugs, for the development of new therapeutic approaches against this human fungal pathogen. This work provides new information about the DNA damage response of the highly important pathogenic fungus C. neoformans.

scholarly journals Chk2-dependent phosphorylation of XRCC1 in the DNA damage response promotes base excision repair

2008 ◽  
Vol 27 (23) ◽  
pp. 3140-3150 ◽  
Author(s):  
Wen-Cheng Chou ◽  
Hui-Chun Wang ◽  
Fen-Hwa Wong ◽  
Shian-ling Ding ◽  
Pei-Ei Wu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Damage Response ◽  
Base Excision

scholarly journals DNA damage response protein ASCIZ links base excision repair with immunoglobulin gene conversion

2008 ◽  
Vol 371 (2) ◽  
pp. 225-229 ◽  
Author(s):  
Hayato Oka ◽  
Wataru Sakai ◽  
Eiichiro Sonoda ◽  
Jun Nakamura ◽  
Kenjiro Asagoshi ◽  
...  
Keyword(s):  
Dna Damage ◽  
Gene Conversion ◽  
Dna Damage Response ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Immunoglobulin Gene ◽  
Damage Response ◽  
Base Excision

scholarly journals Thymine DNA glycosylase modulates DNA damage response and gene expression by base excision repair-dependent and independent mechanisms

2017 ◽  
Vol 22 (4) ◽  
pp. 392-405 ◽  
Author(s):  
Tomohumi Nakamura ◽  
Kouichi Murakami ◽  
Haruto Tada ◽  
Yoshihiko Uehara ◽  
Jumpei Nogami ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Dna Glycosylase ◽  
Thymine Dna Glycosylase ◽  
Damage Response ◽  
Base Excision

scholarly journals Initiation of the ATM-Chk2 DNA damage response through the base excision repair pathway

2015 ◽  
Vol 36 (8) ◽  
pp. 832-840 ◽  
Author(s):  
Wen-Cheng Chou ◽  
Ling-Yueh Hu ◽  
Chia-Ni Hsiung ◽  
Chen-Yang Shen
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Repair Pathway ◽  
Base Excision Repair Pathway ◽  
Damage Response ◽  
Base Excision

scholarly journals XRCC1 Prevents Replication Fork Instability during Misincorporation of the DNA Demethylation Bases 5-Hydroxymethyl-2′-Deoxycytidine and 5-Hydroxymethyl-2′-Deoxyuridine

2022 ◽  
Vol 23 (2) ◽  
pp. 893
Author(s):  
María José Peña-Gómez ◽  
Marina Suárez-Pizarro ◽  
Iván V. Rosado
Keyword(s):  
Genomic Instability ◽  
Base Excision Repair ◽  
Replication Fork ◽  
Genome Stability ◽  
Excision Repair ◽  
Embryonic Stem ◽  
Dna Demethylation ◽  
Dna Bases ◽  
Stem Cell Pluripotency ◽  
Base Excision

Whilst avoidance of chemical modifications of DNA bases is essential to maintain genome stability, during evolution eukaryotic cells have evolved a chemically reversible modification of the cytosine base. These dynamic methylation and demethylation reactions on carbon-5 of cytosine regulate several cellular and developmental processes such as embryonic stem cell pluripotency, cell identity, differentiation or tumourgenesis. Whereas these physiological processes are well characterized, very little is known about the toxicity of these cytosine analogues when they incorporate during replication. Here, we report a role of the base excision repair factor XRCC1 in protecting replication fork upon incorporation of 5-hydroxymethyl-2′-deoxycytosine (5hmC) and its deamination product 5-hydroxymethyl-2′-deoxyuridine (5hmU) during DNA synthesis. In the absence of XRCC1, 5hmC exposure leads to increased genomic instability, replication fork impairment and cell lethality. Moreover, the 5hmC deamination product 5hmU recapitulated the genomic instability phenotypes observed by 5hmC exposure, suggesting that 5hmU accounts for the observed by 5hmC exposure. Remarkably, 5hmC-dependent genomic instability and replication fork impairment seen in Xrcc1−/− cells were exacerbated by the trapping of Parp1 on chromatin, indicating that XRCC1 maintains replication fork stability during processing of 5hmC and 5hmU by the base excision repair pathway. Our findings uncover natural epigenetic DNA bases 5hmC and 5hmU as genotoxic nucleosides that threaten replication dynamics and genome integrity in the absence of XRCC1.

scholarly journals PML Colocalizes with and Stabilizes the DNA Damage Response Protein TopBP1

2003 ◽  
Vol 23 (12) ◽  
pp. 4247-4256 ◽  
Author(s):  
Zhi-Xiang Xu ◽  
Anna Timanova-Atanasova ◽  
Rui-Xun Zhao ◽  
Kun-Sang Chang
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Genome Stability ◽  
Growth Regulation ◽  
Suppressor Gene ◽  
Nuclear Body ◽  
Promyelocytic Leukemia ◽  
Multifunctional Protein ◽  
Damage Response

ABSTRACT The PML tumor suppressor gene is consistently disrupted by t(15;17) in patients with acute promyelocytic leukemia. Promyelocytic leukemia protein (PML) is a multifunctional protein that plays essential roles in cell growth regulation, apoptosis, transcriptional regulation, and genome stability. Our study here shows that PML colocalizes and associates in vivo with the DNA damage response protein TopBP1 in response to ionizing radiation (IR). Both PML and TopBP1 colocalized with the IR-induced bromodeoxyuridine single-stranded DNA foci. PML and TopBP1 also colocalized with Rad50, Brca1, ATM, Rad9, and BLM. IR and interferon (IFN) coinduce the expression levels of both TopBP1 and PML. In PML-deficient NB4 cells, TopBP1 was unable to form IR-induced foci. All-trans-retinoic acid induced reorganization of the PML nuclear body (NB) and reappearance of the IR-induced TopBP1 foci. Inhibition of PML expression by siRNA is associated with a significant decreased in TopBP1 expression. Furthermore, PML-deficient cells express a low level of TopBP1, and its expression cannot be induced by IR or IFN. Adenovirus-mediated overexpression of PML in PML−/− mouse embryo fibroblasts substantially increased TopBP1 expression, which colocalized with the PML NBs. These studies demonstrated a mechanism of PML-dependent expression of TopBP1. PML overexpression induced TopBP1 protein but not the mRNA expression. Pulse-chase labeling analysis demonstrated that PML overexpression stabilized the TopBP1 protein, suggesting that PML plays a role in regulating the stability of TopBP1 in response to IR. Together, our findings demonstrate that PML regulates TopBP1 functions by association and stabilization of the protein in response to IR-induced DNA damage.

scholarly journals DNA damage response and repair in perspective: Aedes aegypti, Drosophila melanogaster and Homo sapiens

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Maria Beatriz S. Mota ◽  
Marcelo Alex Carvalho ◽  
Alvaro N. A. Monteiro ◽  
Rafael D. Mesquita
Keyword(s):  
Dna Damage ◽  
Aedes Aegypti ◽  
Dna Damage Response ◽  
Genetic Manipulation ◽  
Homo Sapiens ◽  
Excision Repair ◽  
Lesion Detection ◽  
Strand Breaks ◽  
Damage Response ◽  
Base Excision

Abstract Background The maintenance of genomic integrity is the responsibility of a complex network, denominated the DNA damage response (DDR), which controls the lesion detection and DNA repair. The main repair pathways are base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), homologous recombination repair (HR) and non-homologous end joining repair (NHEJ). They correct double-strand breaks (DSB), single-strand breaks, mismatches and others, or when the damage is quite extensive and repair insufficient, apoptosis is activated. Methods In this study we used the BLAST reciprocal best-hit methodology to search for DDR orthologs proteins in Aedes aegypti. We also provided a comparison between Ae. aegypti, D. melanogaster and human DDR network. Results Our analysis revealed the presence of ATR and ATM signaling, including the H2AX ortholog, in Ae. aegypti. Key DDR proteins (orthologs to RAD51, Ku and MRN complexes, XP-components, MutS and MutL) were also identified in this insect. Other proteins were not identified in both Ae. aegypti and D. melanogaster, including BRCA1 and its partners from BRCA1-A complex, TP53BP1, PALB2, POLk, CSA, CSB and POLβ. In humans, their absence affects DSB signaling, HR and sub-pathways of NER and BER. Seven orthologs not known in D. melanogaster were found in Ae. aegypti (RNF168, RIF1, WRN, RAD54B, RMI1, DNAPKcs, ARTEMIS). Conclusions The presence of key DDR proteins in Ae. aegypti suggests that the main DDR pathways are functional in this insect, and the identification of proteins not known in D. melanogaster can help fill gaps in the DDR network. The mapping of the DDR network in Ae. aegypti can support mosquito biology studies and inform genetic manipulation approaches applied to this vector.

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