The faithful conservation of genomic information is an essential process for cell survival. Every day more than 10^5 DNA lesions are generated in each cell of our body as a consequence of DNA damage either spontaneously induced during cellular metabolism (e.g., ROS-induced DNA lesions, DNA decay, DNA replication errors) or caused by environmental agents, such as UV radiation (e.g., sunlight), ionizing radiation (e.g., radiotherapy, X-rays, cosmic radiation) and chemical agents (e.g., chemotherapy, tobacco smoking) (Table 1) (Ciccia and Elledge, Mol Cell, 2010).
Table 1. DNA lesions generated by exogenous and endogenous DNA damage (Ciccia and Elledge, Mol Cell, 2010)
THE DNA DAMAGE RESPONSE
To maintain genomic integrity, the signal transduction pathway of the DNA Damage Response (DDR) is activated following DNA damage (Ciccia and Elledge, Mol Cell, 2010). The ATM and ATR kinases are central components of the DDR (Figure 1). ATM is primarily activated by DNA double-stranded breaks (DSBs), while ATR is activated by aberrant replication fork intermediates formed under conditions of DNA replication stress. The DDR promotes genomic stability by regulating a large network of cellular activities, ranging from DNA replication and repair to transcription, RNA splicing and metabolism.
Figure 1. Simplified representation of the DNA damage response
THE DNA DAMAGE RESPONSE IN HUMAN DISEASE
The DDR plays a critical role in human disease. Indeed, mutations in DDR genes cause more than 40 genetic disorders affecting the development of nervous, reproductive and immune systems and predisposing individuals to premature aging and cancer (Table 2) (Ciccia and Elledge, Mol Cell, 2010).
Table 2. Human genetic diseases associated with DDR defects (adapted from Ciccia and Elledge, Mol Cell, 2010)
Identification of novel genetic and proteomic interactions of the DNA damage response
We are currently conducting genetic and proteomic studies to identify novel components of the DNA damage response and define new interactions between DDR pathways. These studies will provide greater insights into the complex mechanisms by which the DDR maintains genomic stability.