Base excision repair accessory factors in senescence avoidance and resistance to treatments

Cancer cells,in which the RAS and PI3K pathways are activated,produce high levels of reactive oxygen species(ROS),which cause oxidative DNA damage and ultimately cellular senescence.This process has been documented in tissue culture,mouse models,and human pre-cancerous lesions.In this context,cellular senescence functions as a tumour suppressor mechanism.Some rare cancer cells,however,manage to adapt to avoid senescence and continue to proliferate.One well-documented mode of adaptation involves increased production of antioxidants often associated with inactivation of the KEAP1 tumour suppressor gene and the resulting upregulation of the NRF2 transcription factor.In this review,we detail an alternative mode of adaptation to oxidative DNA damage induced by ROS:the increased activity of the base excision repair(BER)pathway,achieved through the enhanced expression of BER enzymes and DNA repair accessory factors.These proteins,exemplified here by the CUT domain proteins CUX1,CUX2,and SATB1,stimulate the activity of BER enzymes.The ensued accelerated repair of oxidative DNA damage enables cancer cells to avoid senescence despite high ROS levels.As a by-product of this adaptation,these cancer cells exhibit increased resistance to genotoxic treatments including ionizing radiation,temozolomide,and cisplatin.Moreover,considering the intrinsic error rate associated with DNA repair and translesion synthesis,the elevated number of oxidative DNA lesions caused by high ROS leads to the accumulation of mutations in the cancer cell population,thereby contributing to tumour heterogeneity and eventually to the acquisition of resistance,a major obstacle to clinical treatment.

Cancer stem cells may contribute to the difficulty in treating cancer

Tumour heterogeneity is a phenomenon where each cell that makes up a tumour,contains mutations that differ from that of other cells in the tumour.The clonal evolution and cancer stem cell theories of cancer formation,have been used to explain tumour heterogeneity.The theories both point to the existence of cells within a tumour that are capable of initiating the tumour in a different location.While the clonal evolution theory argues that all cells within a tumour possess this ability,the cancer stem cell theory argues that only a few cells(cancer stem cells or CSCs)within the tumour possess this ability to seed the tumour in a different location.Data supporting the cancer stem cell theory is accumulating.Researchers have targeted these CSCs therapeutically,hypothesizing that since these CSCs are the‘drivers’of tumour progression,their death may inhibit tumour progression.This was foiled by tumour cell plasticity,a phenomenon whereby a non-CSC spontaneously de-differentiates into a CSC.Researchers are now working on combinations that kill both CSCs and non-CSCs as well as drugs that prevent non-CSC-to-CSC transition.This review concisely describes CSCs and how they contribute to the difficulty in treating cancer.