DNA damage response pathway

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Each cell in the human body is subject to tens of thousands of DNA lesions daily. If they are incorrectly repaired, these lesions lead to mutations or genome aberrations that threaten cell or organism viability. To counter threats posed by DNA damage, cells have evolved mechanisms, known collectively as the DNA damage response (DDR), to detect DNA lesions, signal their presence, and promote their repair¹.

DNA damage results from either endogenous sources, such as cellular metabolic processes, or exogenous sources, including environmental factors such as radiation². Numerous proteins and pathways are involved in multiple DNA repair pathways, which correct the different types of DNA damage. Ataxia–telangiectasia-mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) kinases, as well as DNA-dependent protein kinase (DNA-PK), are key for DNA lesion detection. Together with checkpoint kinases, they work to arrest cell-cycle progression by reducing cyclin-dependent kinase (CDK) activity through various mechanisms, some of which are mediated by activating p53¹.  If the damage cannot be removed, apoptosis is triggered.

Many cancers have defects in DDR proteins and pathways, which leave the cell more susceptible to DNA damage. As a result, the cancer cells are more dependent on the remaining pathways, which can lead to tumorigenesis because cancer cells are then more dependent on the remaining pathways. Targeted therapies based on inhibiting the DDR response in patients with tumors lacking specific DDR functions are becoming more prevalent. One such therapy is the poly (ADP-ribose) polymerase (PARP) inhibitor, used to treat tumors harboring BRCA1 or BRCA2 mutations³.

Discover the roles of the key proteins involved in the DDR pathway and find high-quality products to progress your research with our poster.

References

1. Jackson, S.P., Bartek, J. The DNA-damage response in human biology and disease. Nature. 461(7267), 1071-1078 (2009)
2. Hakem, R. DNA-damage repair; the good, the bad, and the ugly. EMBO J. 27(4), 589-605 (2008)
3. O’Connor, M.J. Targeting the DNA Damage Response in Cancer Molecular Cell. 60(4), p.547-560 (2015)