TY - JOUR
T1 - Defective repair of uracil causes telomere defects in mouse hematopoietic cells
AU - Vallabhaneni, Haritha
AU - Zhou, Fang
AU - Maul, Robert W.
AU - Sarkar, Jaya
AU - Yin, Jinhu
AU - Lei, Ming
AU - Harrington, Lea
AU - Gearhart, Patricia J.
AU - Liu, Yie
PY - 2015/2/27
Y1 - 2015/2/27
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M114.607101
DO - 10.1074/jbc.M114.607101
M3 - Article
C2 - 25572391
AN - SCOPUS:84923869937
SN - 0021-9258
VL - 290
SP - 5502
EP - 5511
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 9
ER -