Glioblastoma multiforme is one of the most common tumours affecting the brain and notoriously difficult to cure. It is because glioma cells are particularly resistant to therapy and coupled with the problem of the blood–brain barrier, and the susceptibility of healthy brain tissue to damage during treatment, new adjuvant therapies are clearly needed to tackle this treatment-resistant tumour (Gerstner and Fine, 2007). Photodynamic therapy (PDT) is an emerging adjuvant therapy used in the treatment of different tumours (O'Connor et al, 2009). The PDT has several advantages over traditional treatment regimens. Compared with surgery and radiotherapy, PDT causes less severe long-term morbidity with comparable treatment outcomes (Nyst et al, 2009). It can also be the choice of re-treatment in cases of recurrence and incomplete tumour responses after standard therapies and/or PDT as PDT does not compromise re-treatment effectiveness (Hornung et al, 1998). The PDT uses the excitation of photosensitisers in tumour cells by light to interact with the oxygen in tissues, thus reactive oxygen species are produced to kill the tumour cells through apoptosis or necrosis (Pervaiz, 2001). Photofrin is the most commonly used photosensitiser, and Photofrin-mediated PDT (Ph-PDT) has already been approved for the treatment of different solid tumours by the US Food and Drug Administration (Biel, 2006). Clinical trials using Photofrin to treat gliomas are being carried out, but reports on glioma cell resistance to Ph-PDT in vitro or in vivo are emerging (Adams et al, 1999; Ferrario et al, 2007). This situation is also seen in head and neck dysplasia or cancer patients in which some of them failed to respond, or only partially responded to Ph-PDT (Stylli et al, 2004; Rigual et al, 2009). The underlying cellular mechanisms leading to failure to respond to Ph-PDT are not fully understood. Several proteins and signalling pathways, such as activation of anti-apoptotic proteins, cellular antioxidant defence mechanisms and efflux of photosensitisers by means of P-glycoprotein or ATP-binding cassette transporter proteins have been shown to have significant functions in cellular resistance to Ph-PDT (Saczko et al, 2007a; Usuda et al, 2008, 2010; Zheng et al, 2008). The interactions of these different pathways and proteins may enhance tumour cell proliferation and differentiation, promote invasion and prevent apoptosis, leading to the decreased cytotoxicity of Ph-PDT. The DNA repair has been shown to reduce cell death caused by different cancer therapies, including radiotherapy and chemotherapy using a platinum agent (Frosina, 2009; Fukushima et al, 2009). The Ph-PDT has also been reported to induce significant DNA damage and repair in different cell types (Woods et al, 2004; Saczko et al, 2008). Although different mechanisms have been suggested to explain the causes of resistance in Ph-PDT, the function of DNA repair mechanisms has not been fully investigated. Therefore, we carried out a series of experiments to investigate the DNA repair mechanism(s) that may be responsible for the survival of glioma cells after Ph-PDT. Specific genes representative of the main DNA repair pathways in human beings were examined. The six specific genes are (1) AlkB, alkylation repair homologue 2 (Escherichia coli) (ALKBH2) of direct DNA damage reversal; (2) APEX nuclease (multifunctional DNA repair enzyme) 1 (APEX1) of base excision repair (BER), which removes small base lesions; (3) X-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1) of short-patch BER, which is responsible for repairing single base damage; (4) excision repair cross-complementing rodent repair deficiency, complementation group 5 (ERCC5) of nucleotide excision repair (NER) that repairs bulky, helix-distorting lesions NER; (5) RAD52 homologue (Saccharomyces cerevisiae) (RAD52) of double-strand break repair and (6) REV1 homologue (S. cerevisiae) (REV1) of translesion synthesis, which is a DNA damage tolerance machinery (Christmann et al, 2003). In this study, viable glioma cells recovered 3 h after Ph-PDT were considered as relatively resistant/less responsive to Ph-PDT. The gene ALKBH2, involved in DNA damage reversal, was significantly expressed in these cells for at least 24 h after Ph-PDT. Knockdown of ALKBH2 intensified the cytotoxic effect of Photofrin, which implies that it confers resistance to Ph-PDT. We also showed both mRNA and protein levels of ALKBH2 were up-regulated. This up-regulation was due to the binding of the transcription factor tumour protein (TP53) to one of the predicted promoter regions of ALKBH2, a finding that has not been reported before.