Response to DNA Damage

Cells exposed to ionizing radiation, ultraviolet light or chemicals are prone to acquire multiple sites of bulky DNA lesions and double-strand breaks. Moreover, DNA damaging agents can damage other biomolecules such as proteins, carbohydrates, lipids, and RNA. The accumulation of damage, to be specific, double-strand breaks or adducts stalling thereplication forks, are among known stimulation signals for a global response to DNA damage.[1] The global response to damage is an act directed toward the cells' own preservation and triggers multiple pathways of macromolecular repair, lesion bypass, tolerance, or apoptosis. The common features of global response are induction of multiplegenes, cell cycle arrest, and inhibition of cell division.
Figure 1. Cell response to DNA damage


DNA damage checkpoints

After DNA damage, cell cycle checkpoints are activated. Which has been introduced in the Detection to DNA Damage.

Transcriptional responses to DNA damage

Eukaryotic cells exposed to DNA damaging agents also activate important defensive pathways by inducing multiple proteins involved in DNA repair, cell cycle checkpoint control, protein trafficking and degradation. Such genome wide transcriptional response is very complex and tightly regulated, thus allowing coordinated global response to damage. Exposure of yeast Saccharomyces cerevisiae to DNA damaging agents results in overlapping but distinct transcriptional profiles. Similarities to environmental shock responseindicates that a general global stress response pathway exist at the level of transcriptional activation. In contrast, different human cell types respond to damage differently indicating an absence of a common global response. The probable explanation for this difference between yeast and human cells may be in the heterogeneity of mammalian cells. In an animal different types of cells are distributed among different organs that have evolved different sensitivities to DNA damage.[2]

In general global response to DNA damage involves expression of multiple genes responsible for postreplication repair, homologous recombination, nucleotide excision repair, DNA damage checkpoint, global transcriptional activation, genes controlling mRNA decay, and many others. A large amount of damage to a cell leaves it with an important decision: undergo apoptosis and die, or survive at the cost of living with a modified genome. An increase in tolerance to damage can lead to an increased rate of survival that will allow a greater accumulation of mutations. Yeast Rev1 and human polymerase η are members of [Y family translesion DNA polymerases present during global response to DNA damage and are responsible for enhanced mutagenesis during a global response to DNA damage in eukaryotes.[3]
 


DNA Repair

Which is introduced in the next section Types of DNA Repair

Apoptosis


Apoptosis.png
Figure 2. Apoptosis of a cell

The basic cellular response is to repair the damage, but the type and amount of damage might overwhelm the survival response machinery to the extent that programmed cell death (apoptosis) is initiated instead (Fig. 1). [4]

Following the induction of DNA damage, a prominent route of cell inactivation is apoptosis. During the last ten years, specific DNA lesions that trigger apoptosis have been identified. These include O6-methylguanine, base N-alkylations, bulky DNA adducts, DNA cross-links and DNA double-strand breaks (DSBs).[5]
 
Video below demonstrates  how the cell is being killed upon activation various apoptosis pathway in our body.

YouTube Video

 

1. Lodish H, Berk A, Matsudaira P, Kaiser CA, Krieger M, Scott MP, Zipursky SL, Darnell J. (2004). Molecular Biology of the Cell, p963. WH Freeman: New York, NY. 5th ed.
2. Schlacher, K; Pham, P; Cox, MM; Goodman, MF. (2006). "Roles of DNA Polymerase V and RecA Protein in SOS Damage-Induced Mutation". Chem. Rev 106(2): 406–419.
3. Friedberg EC, Walker GC, Siede W, Wood RD, Schultz RA, Ellenberger T. (2006). DNA Repair and Mutagenesis, part 3. ASM Press. 2nd ed.
4. Yosef Shiloh. (2003). ATM and related protein kinases: safeguarding genome integrity. Nature Reviews Cancer 3, 155-168.
5. Wynand P. Roos and Bernd Kaina. (2006). DNA damage-induced cell death by apoptosis. TRENDS in Molecular Medicine Vol.12 No.9. 440-450
6. Kroemer, G. et al. (2005) Classification of cell death: recommendations of the Nomenclature Committee on Cell Death. Cell Death Differ. 12 (Suppl. 2), 1463–1467
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