Dominguez-Brauer Carmen, Chen Yi-Ju, Brauer Patrick M, Pimkina Julia, Raychaudhuri Pradip
Department of Biochemistry and Molecular Genetics, University of Illinois, College of Medicine, M/C 669, 900 S. Ashland Avenue, Chicago, Illinois 60607, USA.
EMBO Rep. 2009 Sep;10(9):1036-42. doi: 10.1038/embor.2009.139. Epub 2009 Jul 31.
The tumour suppressor ARF (alternative reading frame), which is mutated or silenced in various tumours, has a crucial role in tumour surveillance to suppress unwarranted cell growth and proliferation. ARF has also been linked to the DNA-damage-induced response of p53 because of its ability to inhibit murine double minute 2 (MDM2). Here, however, we provide genetic evidence for a role of ARF in nucleotide excision repair (NER) that is independent of p53. Cells lacking ARF are deficient in NER. Expression of ARF restores the repair activity, which coincides with increased expression of the damaged-DNA recognition protein xeroderma pigmentosum, complementation group C (XPC). We provide evidence that, by disrupting the interaction between E2F transcription factor 4 (E2F4) and DRTF polypeptide 1 (DP1), ARF reduces the interaction of the E2F4-p130 repressor complex with the promoter of XPC to ensure high-level expression of XPC. Together, our results point to an important 'care-taker'-type tumour-suppression function for ARF in NER through the increased expression of XPC.
肿瘤抑制因子ARF（可变阅读框）在多种肿瘤中发生突变或沉默，在肿瘤监测中发挥关键作用，可抑制不必要的细胞生长和增殖。由于ARF能够抑制小鼠双微体2（MDM2），它还与p53的DNA损伤诱导反应有关。然而，在此我们提供了基因证据，表明ARF在核苷酸切除修复（NER）中发挥作用，且该作用独立于p53。缺乏ARF的细胞在NER方面存在缺陷。ARF的表达可恢复修复活性，这与受损DNA识别蛋白着色性干皮病C组（XPC）表达增加相一致。我们提供的证据表明，ARF通过破坏E2F转录因子4（E2F4）与DRTF多肽1（DP1）之间的相互作用，减少E2F4-p130阻遏复合物与XPC启动子的相互作用，以确保XPC的高水平表达。总之，我们的结果表明ARF通过增加XPC的表达，在NER中发挥重要的“守护者”型肿瘤抑制功能。
