RRC ID 56207
Author Papaluca A, Wagner JR, Saragovi HU, Ramotar D.
Title UNG-1 and APN-1 are the major enzymes to efficiently repair 5-hydroxymethyluracil DNA lesions in C. elegans.
Journal Sci Rep
Abstract In Caenorhabditis elegans, two DNA glycosylases, UNG-1 and NTH-1, and two AP endonucleases, APN-1 and EXO-3, have been characterized from the base-excision repair (BER) pathway that repairs oxidatively modified DNA bases. UNG-1 removes uracil, while NTH-1 can remove 5-hydroxymethyluracil (5-hmU), an oxidation product of thymine, as well as other lesions. Both APN-1 and EXO-3 can incise AP sites and remove 3'-blocking lesions at DNA single strand breaks, and only APN-1 possesses 3'- to 5'-exonulease and nucleotide incision repair activities. We used C. elegans mutants to study the role of the BER pathway in processing 5-hmU. We observe that ung-1 mutants exhibited a decrease in brood size and lifespan, and an elevated level of germ cell apoptosis when challenged with 5-hmU. These phenotypes were exacerbated by RNAi downregulation of apn-1 in the ung-1 mutant. The nth-1 or exo-3 mutants displayed wild type phenotypes towards 5-hmU. We show that partially purified UNG-1 can act on 5-hmU lesion in vitro. We propose that UNG-1 removes 5-hmU incorporated into the genome and the resulting AP site is cleaved by APN-1 or EXO-3. In the absence of UNG-1, the 5-hmU is removed by NTH-1 creating a genotoxic 3'-blocking lesion that requires the action of APN-1.
Volume 8(1)
Pages 6860
Published 2018-5-1
DOI 10.1038/s41598-018-25124-1
PII 10.1038/s41598-018-25124-1
PMID 29717169
PMC PMC5931555
MeSH Animals Apoptosis Caenorhabditis elegans* / genetics Caenorhabditis elegans* / metabolism Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* DNA Damage / genetics DNA Glycosylases / genetics DNA Glycosylases / metabolism* DNA Repair / genetics* DNA-(Apurinic or Apyrimidinic Site) Lyase / genetics DNA-(Apurinic or Apyrimidinic Site) Lyase / metabolism* Endodeoxyribonucleases / genetics Endodeoxyribonucleases / metabolism* Endonucleases / genetics Endonucleases / metabolism* Germ Cells / metabolism Longevity / genetics Loss of Function Mutation Pentoxyl / analogs & derivatives Pentoxyl / metabolism Uracil-DNA Glycosidase / genetics Uracil-DNA Glycosidase / metabolism*
IF 4.011
Times Cited 5
C.elegans tm6691 tm4374 tm2862 tm2572