The DNA damage response pathways: at the crossroad of protein modifications

To ensure faithful duplication and inheritance of genetic material, the cell has evolved with the ability to detect and propagate the initial DNA damage signal to elicit cellular responses that include cell cycle arrest, DNA repair, senescence and apoptosis, which collectively have been termed the DNA damage response. Dysregulation of components involved in these processes contributes to genomic instability, which in turn leads to tumorigenesis. This is supported by the fact that clinical mutations in proteins that play a role in the DNA damage response often predispose individuals to cancer development 1. The link between genomic instability and tumorigenesis is perhaps most exemplified by the human genetic disorder ataxia-telangiectasia (A-T). A-T is caused by mutations of the ATM gene, the product of which is intimately involved in the DNA damage signaling network. A-T patients are characterized by neurodegeneration, radiosensitivity, immunodeficiency and cancer predisposition 2, 3. Recent studies indicate that the ATM protein kinase modulates multiple branches of signaling pathways by phosphorylating and regulating its substrates in response to DNA damage, failure of which contributes to genomic instability and tumorigenesis 4. Like ATM, mutations in NBS1 have also been documented to predispose individuals to the genomic instability disorder Nijmegen breakage syndrome (NBS) 5. Patients with hypomorphic mutations in NBS1 manifest microcephaly, immunodeficiency, radiation sensitivity and are prone to carcinogenesis. The close resemblance between NBS and A-T patients suggested a functional relationship between these gene products. Indeed, the MRN complex consisting of Mre11, Rad50 and NBS1 not only has been implicated as one of the initial DNA lesion sensors, but also is believed to be required for efficient ATM activation following DNA damage. As such, the understanding of molecular pathways that function to safeguard the integrity of the genetic material is critical for early detection and offers potential treatments for cancer patients.

http://www.nature.com/cr/journal/v18/n1/full/cr2007109a.html