We have explored how certain telomeric base lesions alter telomere integrity. 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 (BER). Telomeres contain long arrays of TTAGGG repeats and may be susceptible to uracil misincorporation. We have shown that uracil in telomeres weakens the binding by a key telomere binding protein, POT1, which may diminish POT1's ability to inhibit telomerase- or homologous recombination-mediated telomere length maintenance. To explore if uracil interferes with telomere length maintenance, we have examined highly proliferative mouse hematopoietic cells, either defective in Ung or cultured with folic acid depleted medium or anti-folate cancer therapeutic drugs, e.g. pemetrexed, that disrupt folate metabolism. All these conditions increase uracil loads at telomeres and lead to defective telomere length homeostasis. Our data underscore the necessity of Ung-initiated BER for the preservation of telomere length homeostasis in highly proliferative tissues or organs (Vallabhaneni V, et al., Defective repair of uracil causes telomere defects in mouse hematopoietic cells. J. Bio. Chem., 290:5502-11, 2015).
| Long, Juanjuan; Huang, Chenhui; Chen, Yanyan et al. (2017) Telomeric TERB1-TRF1 interaction is crucial for male meiosis. Nat Struct Mol Biol 24:1073-1080 |
| Sarkar, Jaya; Liu, Yie (2016) Fanconi anemia proteins in telomere maintenance. DNA Repair (Amst) 43:107-12 |
| Sarkar, Jaya; Wan, Bingbing; Yin, Jinhu et al. (2015) SLX4 contributes to telomere preservation and regulated processing of telomeric joint molecule intermediates. Nucleic Acids Res 43:5912-23 |
| Vallabhaneni, Haritha; Zhou, Fang; Maul, Robert W et al. (2015) Defective repair of uracil causes telomere defects in mouse hematopoietic cells. J Biol Chem 290:5502-11 |
| Popuri, Venkateswarlu; Hsu, Joseph; Khadka, Prabhat et al. (2014) Human RECQL1 participates in telomere maintenance. Nucleic Acids Res 42:5671-88 |
| Shi, Jianxin; Yang, Xiaohong R; Ballew, Bari et al. (2014) Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma. Nat Genet 46:482-6 |
| Vallabhaneni, Haritha; O'Callaghan, Nathan; Sidorova, Julia et al. (2013) Defective repair of oxidative base lesions by the DNA glycosylase Nth1 associates with multiple telomere defects. PLoS Genet 9:e1003639 |
| Lu, Jian; Vallabhaneni, Haritha; Yin, Jinhu et al. (2013) Deletion of the major peroxiredoxin Tsa1 alters telomere length homeostasis. Aging Cell 12:635-44 |
| Ghosh, Avik K; Rossi, Marie L; Singh, Dharmendra Kumar et al. (2012) RECQL4, the protein mutated in Rothmund-Thomson syndrome, functions in telomere maintenance. J Biol Chem 287:196-209 |
| McNeill, Daniel R; Lin, Ping-Chang; Miller, Marshall G et al. (2011) XRCC1 haploinsufficiency in mice has little effect on aging, but adversely modifies exposure-dependent susceptibility. Nucleic Acids Res 39:7992-8004 |
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