DNA damage (naturally occurring)

See also: Free radical damage to DNA and DNA repair

DNA damage is an alteration in the chemical structure of DNA, such as a break in a strand of DNA, a nucleobase missing from the backbone of DNA, or a chemically changed base such as 8-OHdG. DNA damage can occur naturally or via environmental factors, but is distinctly different from mutation, although both are types of error in DNA. DNA damage is an abnormal chemical structure in DNA, while a mutation is a change in the sequence of base pairs. DNA damages cause changes in the structure of the genetic material and prevents the replication mechanism from functioning and performing properly.[1] The DNA damage response (DDR) is a complex signal transduction pathway which recognizes when DNA is damaged and initiates the cellular response to the damage.[2]

DNA damage and mutation have different biological consequences. While most DNA damages can undergo DNA repair, such repair is not 100% efficient. Un-repaired DNA damages accumulate in non-replicating cells, such as cells in the brains or muscles of adult mammals, and can cause aging.[3][4][5] (Also see DNA damage theory of aging.) In replicating cells, such as cells lining the colon, errors occur upon replication past damages in the template strand of DNA or during repair of DNA damages. These errors can give rise to mutations or epigenetic alterations.[6] Both of these types of alteration can be replicated and passed on to subsequent cell generations. These alterations can change gene function or regulation of gene expression and possibly contribute to progression to cancer.

Throughout the cell cycle there are various checkpoints to ensure the cell is in good condition to progress to mitosis. The three main checkpoints are at G1/s, G2/m, and at the spindle assembly checkpoint regulating progression through anaphase. G1 and G2 checkpoints involve scanning for damaged DNA.[7] During S phase the cell is more vulnerable to DNA damage than any other part of the cell cycle. G2 checkpoint checks for damaged DNA and DNA replication completeness.

  1. ^ Köhler K, Ferreira P, Pfander B, Boos D (2016). "Regulation of the Initiation of DNA Replication upon DNA Damage in Eukaryotes". The Initiation of DNA Replication in Eukaryotes. Springer. pp. 443–460. doi:10.1007/978-3-319-24696-3_22. ISBN 978-3-319-24694-9.
  2. ^ Ciccia A, Elledge SJ (October 2010). "The DNA damage response: making it safe to play with knives". Molecular Cell. 40 (2): 179–204. doi:10.1016/j.molcel.2010.09.019. PMC 2988877. PMID 20965415.
  3. ^ Bernstein H, Payne CM, Bernstein C, Garewal H, Dvorak K (2008). "1. Cancer and aging as consequences of un-repaired DNA damage". In Kimura H, Suzuki A (eds.). New Research on DNA Damages. Nova Science. pp. 1–47. ISBN 978-1-60456-581-2. OCLC 213848806.
  4. ^ Hoeijmakers JH (October 2009). "DNA damage, aging, and cancer". The New England Journal of Medicine. 361 (15): 1475–85. doi:10.1056/NEJMra0804615. PMID 19812404.
  5. ^ Freitas AA, de Magalhães JP (2011). "A review and appraisal of the DNA damage theory of ageing". Mutation Research. 728 (1–2): 12–22. Bibcode:2011MRRMR.728...12F. doi:10.1016/j.mrrev.2011.05.001. PMID 21600302.
  6. ^ O'Hagan HM, Mohammad HP, Baylin SB (August 2008). "Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island". PLOS Genetics. 4 (8): e1000155. doi:10.1371/journal.pgen.1000155. PMC 2491723. PMID 18704159.
  7. ^ "Cell cycle checkpoints". Biology Archive. Khan Academy. Retrieved 2017-12-15.