What causes DNA damage responses (DDRs)?

The DNA Damage Response (DDR) is activated by various types of abnormalities in the genetic material, occurring from physical damage to chemical changes. One source of damage includes ionizing radiation such as X-rays and gamma rays which directly damage DNA by breaking the chemical bonds within the DNA molecules. DDRs can also be caused by base mismatches during DNA replication. These mismatches can occur due to the inherent tendency of DNA polymerases to occasionally insert incorrect nucleotides, despite their proofreading mechanisms. Another abnormality arises from DNA strand breaks caused by topoisomerase I and II. Topoisomerase I generates single-strand breaks (SSBs) by cleaving one strand of the DNA double helix. Although these breaks are normally resealed by topoisomerase I after DNA relaxation, malfunctioning activity can result in incomplete resealing, leading to SSBs. Toposiomerase II creates double-strand breaks (DSBs) into DNA. If topoisomerase II activity is impaired or if the enzyme becomes trapped on DNA, it can result in the accumulation of DSBs. Overall, Unrepaired or improperly repaired DNA strand breaks can lead to genomic instability. Another source are chemical agents. Certain chemicals such as those found in tobacco smoke, environmental pollutants, and some chemotherapy drugs, can directly damage DNA. Additionally, reactive oxygen species (ROS) are generated during normal cellular metabolism and can cause oxidative damage to DNA. ROS easily damages DNA by creating a variety of lesions, such as oxidized bases and breaks in the DNA strands. Lastly, UV radiation from sunlight can cause damage to DNA, leading to the formation of thymine dimers and other lesions.