Cabelof Lab

Here’s the amazing transformation of my lab:

 

 

 

 

 

 

 

 

 

DNA Base Excision Repair, DNA polymerase beta, and aging:

My prior research investigated the impact of endogenous DNA damage on aging in several model systems.  My dissertation work included the first report that DNA base excision repair (BER) capacity declines significantly with age; and, that caloric restriction could reverse that decline.  Subsequently we identified that heterozygous loss of DNA polymerase β (polβ) accelerates the onset of age-dependent lymphoma and accelerates the mortality rate.  This data provided the foundation for my hypothesis that loss of BER might be causative in the premature aging observed in Down syndrome.  I have also reported that aging animals have an inability to mount a BER response to DNA damage (oxidative stress), and that this inability may be linked to age-dependent mutation burden.   I have worked to understand both what causes the inability to mount a DNA repair response in old animals, and what the consequences of this might be on longevity and/or disease burden. The final NIH project I had before changing research focus, investigated the impact of BER deficiency on the accelerated aging observed in Down syndrome.  This work provided mechanistic evidence in favor of reduced DNA repair as causative in accelerated senescence.

Former Key Personnel/Lab Members:

Cristine Smoczer, MD, PhD: past postdoctoral fellow

 

 

 

 

 

 

Hongzhi Ma, PhD: past PhD student

Thesis: Folate and Genome Instability, 2013

 

 

 

 

Aqila Ahmed, PhD: past PhD student

Thesis: Down syndrome, Aging, and Base Excision Repair, 2016

 

 

 

 

 

Liz Zanley, MS, RD: Past MS student

Thesis: Folate Depletion: Uracil, dNTP Imbalance, and Cell Cycle, 2019

 

 

 

 

 

Ghada Aoun, MS: Past MS student

Thesis: Impact of Folate Depletion on Tissue Folate Status, 2015

 

 

 

 

Bri Pace, MS: Past MS student

Thesis: DNA Repair and Senescence in Down Syndrome, 2018

 

 

 

 

Khadijah Alnabbat, MS: Past MS student

Thesis: Folate, Ribonucleotides, and Down Syndrome, 2015

Publications:

  1. Cabelof, C. (1994). Preventing infection from foodborne pathogens in liver transplant patients. J. American Dietetic Association, 94(10): 1140-4.
  2. Cabelof D.C., Raffoul J.J., Yanamadala S., Ganir C., Guo Z., Heydari, A.R. (2002). Attenuation in DNA polymerase b-dependent base excision repair pathway and increased DMS induced mutagenicity in aged mice. Mutation Research, 500:135-145.
  3. Cabelof C., Raffoul J.J., Yanamadala S., Guo Z., Heydari, A.R. (2002). Role of DNA polymerase b-dependent base excision repair in response to 2-nitropropane. Carcinogenesis, 23:1419-1425.
  4. Cabelof D.C., Yanamadala S., Raffoul J.J., Soofi A.S., Guo Z., Heydari, A.R. (2003). Caloric restriction promotes genetic stability by induction of base excision repair and reversal of its age-related decline. DNA Repair 2:295-307.
  5. Cabelof D.C., Guo Z. Raffoul J.J., Sobol R.W., Wilson, S.H., Richardson, A., Heydari, A.R. (2003). Base excision repair deficiency caused by polymerase β haploinsufficiency: Accelerated DNA damage and increased mutational response to carcinogens. Cancer Research, 63: 5799-5807.
  6. Raffoul J.J., Cabelof D.C., Nakamura J., Meira L.B., Friedberg E.C., Heydari, A.R. (2004). Apurinic/apyrimidinic endonuclease (APE/ref-1) haploinsufficient mice display tissue-specific differences in DNA polymerase β-dependent base excision repair. Biol. Chem, 279:18425-18433.
  7. Cabelof, D.C., Raffoul, J.J., Nakamura, J., Kapoor, D., Abdalla, H., Heydari, A.R. (2004) Imbalanced base excision repair in response to folate deficiency is accelerated by polymerase beta haploinsufficiency. J Biol Chem, 279:36504-36513.
  8. Liu, M., Ge, Y., Cabelof, D.C., Aboukameel, A., Heydari, A.R., Mohammad, R., Matherly, L.H. (2005): Structure and regulation of the murine reduced folate carrier gene: identification of 4 non-coding exons and promoters and regulation by dietary folates, Biol. Chem. 280: 5588-5597.
  9. Cabelof, C., Nakamura J., Heydari, A.R. (2006) Development of a sensitive biochemical assay for the detection of uracil in DNA. Environmental and Molecular Mutagenesis, 47:31-7.
  10. Cabelof, C., Raffoul, J.J., Ge, Y., Van Remmen, H., Matherly, L.H., Heydari, A.R. (2006). Age-related loss of the DNA repair response following exposure to oxidative stress. J Gerontology, A Biol Sci. Med. Sci. 61:427-434.
  11. Cabelof, D.C., Ikeno, Y., Nyska, A., Busuttil, R.A., Anyanagwe, N., Vijg, J., Matherly, L.H., Tucker, J.D., Wilson, S.H., Richardson, A., Heydari, A.R. (2006) Haploinsufficiency in DNA polymerase β increases cancer risk with age and alters mortality rate. Cancer Research 66:7460-7465.
  12. Kanellis, P., Gagliardi, M., Banath, J.P., Szilard, R.K., Nakada, S., Galicia, S., Sweeney, F.D., Cabelof, C., Olive, P.L., Durocher, D. (2007) A screen for suppressors of gross chromosomal rearrangements identifies a conserved role for PLP in preventing DNA lesions. PLoS Genet 3: 1438-1453.
  13. Cabelof, C. (2007) Aging and base excision repair: In need of a comprehensive approach. DNA Repair (Amst). 6:1399-402.
  14. Qui, A., Min, S., Jansen, M., Malhotra, U., Tsai, E., Cabelof, C., Matherly, L.H., Zhao, R., Akabas, M.H., Goldman, I.D. (2007) Rodent intestinal folate transporters (SLC46A1): secondary structure, functional properties, response to dietary folate restriction. Am J Physiol Cell Physio 293:1669-78.
  15. Unnikrishnan, A., Raffoul, J.J., Patel, H.V., Prychitko, T.M., Anyangwe, N., Meira, L.B., Friedberg, E.C., Cabelof, D.C., Heydari, A.R. (2009) Oxidative stress alters base excision repair pathway and increases apoptotic response in Apurinin/apyrimidinic endonuclease 1/Redox factor-1 haploinsufficient mice. Free Rad Biol Med 46:1488-99.
  16. Cabelof DC, Chen Q, Ge Y, van Remmen H, Matherly LH, and Taub JW (2009) Mutational spectrum at GATA1 provides insights into mutagenesis and leukemogenesis in Down syndrome. Blood 114:2753-63.
  17. Simon K, Dewundara S, van Remmen H, Dombkowski AA, and Cabelof DC (2009) Transcriptional profiling of the age-related response to genotoxic stress points o differential DNA damage response with age. Mech Ageing Dev 130: 637-47.
  18. Lucente LV, Unnikrishnan A, Pilling AB, Patel HV, Kushwaha D, Dombkowski A, Schmelz EM, Cabelof DC, Heydari AR (2010). Folate deficiency provides protection against colon carcinogenesis in DNA polymerase β haploinsufficient mice. J Biol Chem. 285:19246-58.
  19. Unnikrishnan KA, Prychitko TM, Patel HV, Chowdhury ME, Pilling AB, Ventrella-Lucente LF, Papakonstantionu EV, Cabelof DC, and Heydari AR (2011) Folate deficiency regulates expression of DNA polymerase β in response to oxidative stress. Free Radic Biol Med 50:270-80.
  20. Cabelof DC (2012) Haploinsufficiency in mouse models of DNA repair deficiency: modifiers of penetrance. Cell Mol Life Sci 69:727-40.
  21. Simon KW, Ma H, Dombkowski AA and Cabelof DC (2012) Aging alters folate homeostasis and DNA damage response in colon. Mech Ageing Dev 133:75-82.
  22. Patterson D and Cabelof DC (2012) Down syndrome as a model of DNA polymerase beta haploinsufficiency and accelerated aging. Mech Ageing Dev 133:133-7.
  23. Rosati, R, Ma H and Cabelof DC (2012) Folate and colorectal cancer in rodents: a model of DNA repair deficiency, J Oncology 2012.
  24. Ahmed, AA, Smoczer C, Pace B, Patterson D and Cress (Cabelof) D (2018) Loss of DNA polymeraseβ induces senescence, Environmental and Molecular Mutagenesis 59:603-12.