Defective repair of uracil causes telomere defects in mouse hematopoietic cells

Haritha Vallabhaneni, Fang Zhou, Robert W. Maul, Jaya Sarkar, Jinhu Yin, Ming Lei, Lea Harrington, Patricia J. Gearhart, Yie Liu

Research output: Contribution to journalArticle

Abstract

Uracil in the genome can result from misincorporation of dUTP instead of dTTP during DNA synthesis, and is primarily removed by uracil DNA glycosylase (UNG) during base excision repair. Telomeres contain long arrays of TTAGGG repeats and may be susceptible to uracil misincorporation. Using model telomeric DNA substrates, we showed that the position and number of uracil substitutions of thymine in telomeric DNA decreased recognition by the telomere single-strand binding protein, POT1. In primary mouse hematopoietic cells, uracil was detectable at telomeres, and UNG deficiency further increased uracil loads and led to abnormal telomere lengthening. In UNG-deficient cells, the frequencies of sister chromatid exchange and fragility in telomeres also significantly increased in the absence of telomerase. Thus, accumulation of uracil and/or UNG deficiency interferes with telomere maintenance, thereby underscoring the necessity of UNG-initiated base excision repair for the preservation of telomere integrity.

Original languageEnglish (US)
Pages (from-to)5502-5511
Number of pages10
JournalJournal of Biological Chemistry
Volume290
Issue number9
DOIs
StatePublished - Feb 27 2015
Externally publishedYes

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Uracil-DNA Glycosidase
Uracil
Telomere
Repair
Defects
DNA Repair
DNA
Telomere Homeostasis
Sister Chromatid Exchange
Thymine
Telomerase
Carrier Proteins
Substitution reactions
Genes
Maintenance
Genome
Substrates

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Vallabhaneni, H., Zhou, F., Maul, R. W., Sarkar, J., Yin, J., Lei, M., ... Liu, Y. (2015). Defective repair of uracil causes telomere defects in mouse hematopoietic cells. Journal of Biological Chemistry, 290(9), 5502-5511. https://doi.org/10.1074/jbc.M114.607101

Defective repair of uracil causes telomere defects in mouse hematopoietic cells. / Vallabhaneni, Haritha; Zhou, Fang; Maul, Robert W.; Sarkar, Jaya; Yin, Jinhu; Lei, Ming; Harrington, Lea; Gearhart, Patricia J.; Liu, Yie.

In: Journal of Biological Chemistry, Vol. 290, No. 9, 27.02.2015, p. 5502-5511.

Research output: Contribution to journalArticle

Vallabhaneni, H, Zhou, F, Maul, RW, Sarkar, J, Yin, J, Lei, M, Harrington, L, Gearhart, PJ & Liu, Y 2015, 'Defective repair of uracil causes telomere defects in mouse hematopoietic cells', Journal of Biological Chemistry, vol. 290, no. 9, pp. 5502-5511. https://doi.org/10.1074/jbc.M114.607101
Vallabhaneni, Haritha ; Zhou, Fang ; Maul, Robert W. ; Sarkar, Jaya ; Yin, Jinhu ; Lei, Ming ; Harrington, Lea ; Gearhart, Patricia J. ; Liu, Yie. / Defective repair of uracil causes telomere defects in mouse hematopoietic cells. In: Journal of Biological Chemistry. 2015 ; Vol. 290, No. 9. pp. 5502-5511.
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