Base excision DNA repair and cancer

Transformed cells can develop drug resistance via repair mechanisms that counteract the DNA damage from chemotherapy or radiation therapy. Disruption of DNA repair pathways can cause mis-repair that is cytotoxic [1]. Specific DNA repair inhibitors might thus be combined with DNA-damaging agents for improved therapy. In addition, some cancer cells have a reduced repertoire of DNA damage responses, which provides other therapeutic openings. Recent studies show that many DNA repair proteins are associated with those involved in RNA metabolism and transcriptional regulation, including within the nucleolus [2]. The base excision DNA repair (BER) pathway handles simple alkylation and oxidative lesions arising from both endogenous and exogenous sources, including cancer therapy agents. The core BER enzyme Ape1 also contributes to the regulation of oxidative stress responses and has other non-repair activities, such as regulating the expression of chemoresistance genes (i.e. MDR1) [3]. Ape1 is thus an emerging target for combination therapy of different cancers. Ape1 can function as a " redox factor " [1] that stimulates DNA binding by transcription factors involved in cancer promotion and progression, such as NF-ĸB, Egr-1, Hif-1α, Nrf1 [3], thus influencing inflammatory and metastatic processes. A third poorly characterized Ape1 function is its transcriptional activity on genes such as SIRT1 and those encoding some mitochondrial proteins (Tfam, Cox6c, and Tomm22) [2]. Moreover, Ape1 regulates the expression of tumor-progression and therapy-resistance genes through transcriptional effects (on the VEGF and MDR1 genes, for example) and post-transcriptional mechanisms through direct mRNA binding by Ape1 (e.g. c-Myc) [3]. These observations prompt a new model that links DNA damage responses and the modulation of target genes, which may provide chemoresistance during tumor development. Cancer-associated Ape1 variants are often altered in the protein's DNA repair domain, with some exhibiting nuclease defects in vitro [4]. Up-regulation of Ape1 correlates with the onset of chemoresistance in ovarian, hepatic and neurologic tumors, while inhibition of the protein with small compounds, or the downregulation of its expression, sensitizes cells to DNA-damaging chemotherapeutic drugs and ionizing radiation [3]. Which Ape1 activity is involved in cancer development or chemoresistance remains unknown. We discovered a function of Ape1 in rRNA metabolism involving direct rRNA binding and interaction with NPM1, which is required for retaining Ape1 in the nucleolus. A role in rRNA metabolism may explain the altered Ape1 expression observed in different tumors [3]. Although knowledge of Ape1's possible function in the nucleolus is incomplete, the protein retained there …