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Critical Reviews™ in Oncogenesis

ISSN Print: 0893-9675
ISSN Online: 2162-6448

Critical Reviews™ in Oncogenesis

DOI: 10.1615/CritRevOncog.v14.i4.20
pages 217-273

The Contribution of DNA Base Damage to Human Cancer Is Modulated by the Base Excision Repair Interaction Network

Katarzyna D. Arczewska
University of Oslo, The Biotechnology Centre, Norway; and Institute of Biochemistry and Biophysics PAS, Poland
Katerina Michalickova
University of Oslo, The Biotechnology Centre, Norway
Ian M. Donaldson
University of Oslo, The Biotechnology Centre, Norway
Hilde Nilsen
University of Oslo, The Biotechnology Centre, Norway

ABSTRACT

Base excision repair (BER) is a major mode of repair of DNA base damage. BER is required for maintenance of genetic stability, which is important in the prevention of cancer. However, direct genetic associations between BER deficiency and human cancer have been difficult to firmly establish, and the first-generation mouse models deficient in individual DNA-glycosylases, which are the enzymes that give lesion specificity to the BER pathway, generally do not develop spontaneous tumors. This review summarizes our current understanding of the contribution of DNA base damage to human cancer, with a particular focus on DNA-glycosylases and two of the main enzymes that prevent misincorporation of damaged deoxynucleotide triphosphates into DNA: the dUTPase and MTH1. The available evidence suggests that the most important factors determining individual susceptibility to cancer are not mutations in individual DNA repair enzymes but rather the regulation of expression and modulation of function by protein modification and interaction partners. With this in mind, we present a comprehensive list of protein-protein interactions involving DNA-glycosylases or either of the two enzymes that limit incorporation of damaged nucleotides into DNA. Interacting partners with a known role in human cancer are specifically highlighted.