UNG-1 and APN-1 are the major enzymes to efficiently repair 5-hydroxymethyluracil DNA lesions in C. elegans

Papaluca, Arturo; Wagner, Jeffrey; Saragovi, H. Uri; Ramotar, Dindial

doi:10.1038/s41598-018-25124-1

Cited by 14 publications

(16 citation statements)

References 51 publications

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“…The dinoflagellates have both mono-functional and bi-functional glycosylases (Figure 3 and Table 3). The glycosylases targeting uracil and its derivatives including UNG [76], SMUG1 [77], MBD4 [78], TDG [77,78] and NTH1 [79], are of special interest. These genes were reported to have activities against 5hmu.…”

Section: Resultsmentioning

confidence: 99%

DNA Damage Response Pathways in Dinoflagellates

Wong

2019

Microorganisms

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Dinoflagellates are a general group of phytoplankton, ubiquitous in aquatic environments. Most dinoflagellates are non-obligate autotrophs, subjected to potential physical and chemical DNA-damaging agents, including UV irradiation, in the euphotic zone. Delay of cell cycles by irradiation, as part of DNA damage responses (DDRs), could potentially lead to growth inhibition, contributing to major errors in the estimation of primary productivity and interpretations of photo-inhibition. Their liquid crystalline chromosomes (LCCs) have large amount of abnormal bases, restricted placement of coding sequences at the chromosomes periphery, and tandem repeat-encoded genes. These chromosome characteristics, their large genome sizes, as well as the lack of architectural nucleosomes, likely contribute to possible differential responses to DNA damage agents. In this study, we sought potential dinoflagellate orthologues of eukaryotic DNA damage repair pathways, and the linking pathway with cell-cycle control in three dinoflagellate species. It appeared that major orthologues in photoreactivation, base excision repair, nucleotide excision repair, mismatch repair, double-strand break repair and homologous recombination repair are well represented in dinoflagellate genomes. Future studies should address possible differential DNA damage responses of dinoflagellates over other planktonic groups, especially in relation to possible shift of life-cycle transitions in responses to UV irradiation. This may have a potential role in the persistence of dinoflagellate red tides with the advent of climatic change.

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Section: Resultsmentioning

confidence: 99%

DNA Damage Response Pathways in Dinoflagellates

Wong

2019

Microorganisms

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“…Several years later, the ung-1 and nth -1 genes encoding U racil D N A G lycosylase UNG-1 and E n donuclease III NTH-1, respectively, were identified and characterized in C. elegans ( Nakamura et al, 2008 ; Morinaga et al, 2009 ). Despite several attempts, including extensive homology searches and most importantly enzymatic assays designed to remove specific DNA lesions such as 8-oxoGuanine, no other DNA glycosylases have been found in C. elegans besides UNG-1 and NTH-1 ( Denver et al, 2003 ; Papaluca et al, 2018 ). It seems puzzling that this multicellular organism conserved only two DNA glycosylases when the unicellular E. coli , the budding yeast S. cerevisiae and human cells have conserved eight, five and eleven DNA glycosylases, respectively ( Denver et al, 2003 ; Wallace, 2014 ).…”

Section: Dna Glycosylases In C Elegansmentioning

confidence: 99%

“…Recently, it has been reported that UNG-1 may possess the ability to process the oxidized base lesion 5-hmU. This is based on phenotypic analysis of C. elegans ung-1 mutant showing decreased survival upon exposure to the nucleoside form of 5-hmU ( Papaluca et al, 2018 ). We propose that C. elegans UNG-1, unlike Ung from other organisms, may have evolved to acquire a broader substrate specificity and thus could act as the dominant DNA glycosylase in vivo to remove various modified forms of uracil such as the 5-hmU lesion.…”

Section: Dna Glycosylases In C Elegansmentioning

confidence: 99%

“…C. elegans UNG-1 shares a modest 12.6% identity with SMUG1 ( Zauri et al, 2015 ). A closer examination of the identity revealed that C. elegans UNG-1 shares five amino acid residues Ser58, Pro218, Gly226, Glu233, and Leu234 that are unique to human SMUG1 residues Ser48, Pro166, Gly174, Glu181 and Leu182 and which are absent in human UNG1 ( Papaluca et al, 2018 ). Whether these five amino acid residues are involved in conferring upon C. elegans UNG-1 the ability to recognize and process 5-hmU in a manner similar to human SMUG1 will need to be investigated.…”

Section: Dna Glycosylases In C Elegansmentioning

confidence: 99%

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The Base Excision Repair Pathway in the Nematode Caenorhabditis elegans

Elsakrmy

Zhang-Akiyama

Ramotar

2020

Front. Cell Dev. Biol.

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Exogenous and endogenous damage to the DNA is inevitable. Several DNA repair pathways including base excision, nucleotide excision, mismatch, homologous and non-homologous recombinations are conserved across all organisms to faithfully maintain the integrity of the genome. The base excision repair (BER) pathway functions to repair single-base DNA lesions and during the process creates the premutagenic apurinic/apyrimidinic (AP) sites. In this review, we discuss the components of the BER pathway in the nematode Caenorhabditis elegans and delineate the different phenotypes caused by the deletion or the knockdown of the respective DNA repair gene, as well as the implications. To date, two DNA glycosylases have been identified in C. elegans, the monofunctional uracil DNA glycosylase-1 (UNG-1) and the bifunctional endonuclease III-1 (NTH-1) with associated AP lyase activity. In addition, the animal possesses two AP endonucleases belonging to the exonuclease-3 and endonuclease IV families and in C. elegans these enzymes are called EXO-3 and APN-1, respectively. In mammalian cells, the DNA polymerase, Pol beta, that is required to reinsert the correct bases for DNA repair synthesis is not found in the genome of C. elegans and the evidence indicates that this role could be substituted by DNA polymerase theta (POLQ), which is known to perform a function in the microhomology-mediated end-joining pathway in human cells. The phenotypes observed by the C. elegans mutant strains of the BER pathway raised many challenging questions including the possibility that the DNA glycosylases may have broader functional roles, as discuss in this review.

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“…Additionally, it has also been proposed that HMdU present in double-helical DNA might cause genomic instability as it can form potentially mutagenic lesions and destabilize double-helical DNA [16]. However, this formation of mutagenic and DNA destabilizing lesions is not due to the intrinsic properties of HMdU, but is as a consequence of its removal by DNA repair enzymes [17,18] and subsequent errors arising during its repair [19]. Notably, HMdU is one of several recently discovered epigenetic modifications [11,13].…”

Section: Introductionmentioning

confidence: 99%

Translesion DNA Synthesis Across Lesions Induced by Oxidative Products of Pyrimidines: An Insight into the Mechanism by Microscale Thermophoresis

Hrabina

Brabec

Nováková

2019

IJMS

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Oxidative stress in cells can lead to the accumulation of reactive oxygen species and oxidation of DNA precursors. Oxidized nucleotides such as 2’-deoxyribo-5-hydroxyuridin (HdU) and 2’-deoxyribo-5-hydroxymethyluridin (HMdU) can be inserted into DNA during replication and repair. HdU and HMdU have attracted particular interest because they have different effects on damaged-DNA processing enzymes that control the downstream effects of the lesions. Herein, we studied the chemically simulated translesion DNA synthesis (TLS) across the lesions formed by HdU or HMdU using microscale thermophoresis (MST). The thermodynamic changes associated with replication across HdU or HMdU show that the HdU paired with the mismatched deoxyribonucleoside triphosphates disturbs DNA duplexes considerably less than thymidine (dT) or HMdU. Moreover, we also demonstrate that TLS by DNA polymerases across the lesion derived from HdU was markedly less extensive and potentially more mutagenic than that across the lesion formed by HMdU. Thus, DNA polymerization by DNA polymerase η (polη), the exonuclease-deficient Klenow fragment of DNA polymerase I (KF–), and reverse transcriptase from human immunodeficiency virus type 1 (HIV-1 RT) across these pyrimidine lesions correlated with the different stabilization effects of the HdU and HMdU in DNA duplexes revealed by MST. The equilibrium thermodynamic data obtained by MST can explain the influence of the thermodynamic alterations on the ability of DNA polymerases to bypass lesions induced by oxidative products of pyrimidines. The results also highlighted the usefulness of MST in evaluating the impact of oxidative products of pyrimidines on the processing of these lesions by damaged DNA processing enzymes.

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UNG-1 and APN-1 are the major enzymes to efficiently repair 5-hydroxymethyluracil DNA lesions in C. elegans

Cited by 14 publications

References 51 publications

DNA Damage Response Pathways in Dinoflagellates

DNA Damage Response Pathways in Dinoflagellates

The Base Excision Repair Pathway in the Nematode Caenorhabditis elegans

Translesion DNA Synthesis Across Lesions Induced by Oxidative Products of Pyrimidines: An Insight into the Mechanism by Microscale Thermophoresis

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