Cancer is defined as a group of diseases principally characterised by uncontrolled cellular proliferation driving the perpetual transformation of normal cells into malignant counterparts through a complex multi-step process. In addition to previously defined hallmarks of cancer, the sheer volume of reports suggests additional “enabling and emerging characteristics of cancer” such as genomic instability by virtue of amplified oncogenic mutation incidences. Numerous molecular events involved in the cell cycle regulation and DNA damage response (DDR) have been identified to preserve cell survival and genome integrity. Therefore, mammalian cells employ various molecular mechanisms to distinguish DNA replication into the synthesis (S) phase from the equal distribution of identical genetic materials during the mitosis (M) phase. These distinct set of specialised biochemical events are coordinated by the activities of cyclin-dependent kinases (CDKs) and cell cycle phase specific cyclins, two key regulatory molecules of the cell cycle progression.
In addition to deficient genome replication and/or chromosome segregation, the genetic integrity is also being constantly threatened by both spontaneously induced endogenous DNA damage (e.g. replication stress, oxygen free radicals, endogenous alkylating agents) or exogenous physical and chemical DNA damaging factors (ionising radiation, chemotherapeutics etc.). Mammalian cells utilise a complex signalling network to detect, signal and repair DNA damage with the aim of restoring genomic stability. In case the DNA damage is beyond repair, the damaged cell is removed from the proliferating cell pool through the means of programmed cell death or cellular senescence. However, if the cells fail to repair DNA and/or promote cell death/senescence, mutations may arise and accumulate within the genome, consequently resulting in the dysregulation of several genes that are responsible for regulating cell growth, proliferation and/or death, which in turn would increase the risk of tumour development and progression as well as development of other diseases.
The DDR cascade has a number of different components determining, depending on the magnitude of DNA damage and the cell type, the outcome in cells with damaged DNA. The DDR constituents are responsible for: (i) rapid damage detection to trigger activation of signalling pathways and induction of cell cycle checkpoints, and (ii) DNA damage repair or (iii) activation of apoptotic pathways to eliminate terminally damaged cells. Thus, it appears to be vital to understand better the DDR coordination, since this would allow us to improve the outcome of cancer treatment in the context of manipulating DDR within the cell cycle checkpoints, specifically the DDR components that cancer cells tend to rely on for their survival.
There are a number of major problems with conventional chemotherapy drugs that are widely used in the clinic. For example, chemotherapy agents do not specifically and selectively kill tumour cells, since they can also potentially target normal cells, especially rapidly dividing healthy cells such as those present in the bone marrow and hair follicles. The cancer cells forming the tumour mass are generally in different cell cycle stages and often have different transcriptional profiles of genes involved in significant biological processes. These intra-tumour heterogeneities, although mostly ignored by conventional cancer treatments, can affect the outcome of the cellular response to radio- and chemotherapeutics. Therefore, further understanding of the molecular and biochemical mechanisms driving the treatment response has become crucial in the management of cancer treatment. To understand mechanisms that control genome stability in response to DNA damage, our work focus on elucidating the molecular regulation of key pathways including cell cycle regulation, DNA damage response and repair, and programmed cell death.
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