Repair of damaged DNA is critical for maintaining genomic integrity and thereby preventing the propagation of mutations, either horizontally (somatic cells), or vertically (germ cells). DNA is subjected to a huge array of chemical, physical, and biologic assaults on a daily basis (Table 1), hence efficient recognition and repair of DNA lesions is essential. Consequently, eukaryotic cells contain five major DNA repair pathways, each of which contain multiple, sometimes shared proteins; these DNA repair proteins typically have orthologues in prokaryotes. The mechanisms of DNA repair includenucleotide excision repair (NER); mismatch repair (MMR); base excision repair (BER); homologous recombination (HR); and nonhomologous end-joining (NHEJ) repair pathways (Figure 1). The experiment of testing the importance of many of these DNA repair proteins to human biology has been performed by nature—mutations in a large number of these genes lead to human disease (Table 2). Moreover, systematic gene-directed “knockout” experiments with laboratory mice and cells in culture have clearly ascribed critical genome integrity maintenance functions to these genes as well. In these genetic studies, it was observed that indeed targeted mutations within these genes induce defects in DNA repair while often also dramatically increasing susceptibility to cancer.

Table1. Types of Damage to DNA

Fig1. Mammals use multiple DNA repair pathways of variable accuracy to repair the myriad forms of DNA damage that genomic DNA is subjected to. Listed are the major types of DNA damaging agents, the DNA lesions so formed (schematized and listed), the DNA repair pathway responsible for repairing the different lesions, and the relative fidelity of these pathways. (Reproduced with permission from Blanpain C, Mohrin M, Sotiropoulou PA, et al: DNA-damage response in tissue-specific and cancer stem cells. Cell Stem Cell. 2011;8(1):16-29.)

Table2. Human Diseases of DNA Damage Repair

One of the most intensively studied mechanisms of DNA repair is the mechanism used to repair DNA double-strand breaks (DSBs). DSBs are DNA damage events that are highly mutagenic, and will be discussed in some detail here. There are two pathways, HR and NHEJ, that eukaryotic cells utilize to remove DSBs. The choice between the two depends on the phase of the cell cycle and the exact type of DSB breaks to be repaired (Table 1). During the G0 /G1 phases of the cell cycle, DSBs are corrected by the NHEJ pathway, whereas during S, G2 , and M phases of the cell cycle HR is utilized. All steps of DNA damage repair are catalyzed by evolutionarily conserved molecules, which include DNA damage sensors, transducers, and damage repair mediators. Collectively, these cascades of proteins participate in the cellular response to DNA damage. Importantly, the ultimate cellular outcomes of DNA damage, and cellular attempts to repair DNA damage, range from cell cycle delay to allow for DNA repair, to cell-cycle arrest, to apoptosis or senescence (Figure 2; and further detail in following discussion). The molecules involved in these com plex and highly integrated processes range from recognition of damage-specific histone modifications (ie, dimethylated lysine 20 histone H4; H4K20me2) and incorporation of histone iso type variants such as histone H2AX into nucleosomes at the site of DNA damage, poly ADP ribose polymerase (PARP), the MRN protein complex (Mre11-Rad50 NBS1 subunits); to DNA damage-activated kinase recognition/ signaling proteins (ATM [ataxia telangiectasia, mutated] and ATM-related kinase (ATR), the multisubunit DNA-dependent protein kinase [DNA-PK and Ku70/80], and checkpoint kinases 1 and 2 [CHK1, CHK2]). These multiple kinases phosphorylate and consequently modulate the activities of dozens of proteins, such as numerous DNA repair, checkpoint control, and cell-cycle control proteins like CDC25A, B, C, Wee1, p21, p16, and p19 (all cyclin–CDK regulators [see Figure 9–8; and following discussion]; various exo- and endonucleases; DNA single-strand-specific DNA-binding proteins [RPA]; PCNA and specific DNA polymerases [DNA pol δ and η]). Several of these (types of) proteins/enzymes have been dis cussed earlier in the context of DNA replication. DNA repair and its relationship to cell-cycle control are very active areas of research given their central roles in cell biology and potential for generating and preventing cancer.

Fig2. The multistep mechanism of DNA double-strand break repair. Shown top to bottom are the proteins (protein complexes) that identify DSBs in genomic DNA (sensors), transduce, and amplify the recognized DNA damage (transducers and mediators), as well as the molecules that dictate the ultimate outcomes of the DNA damage response (effectors). Damaged DNA can be (a) repaired directly (DNA repair), or, via p53-mediated pathways and depending on the severity of DNA damage and p53-activated genes induced, (b), cells can be arrested in the cell cycle by p21/WAF1 the potent CDK–cyclin complex inhibitor to allow time for extensively damaged DNA to be repaired, or (c), and (d) if the extent of DNA damage is too great to repair, cells can either undergo apoptosis (programmed cell death) or senescence (gradual loss of viability due to cessation of cell division). Both of these processes prevent the cell containing such damaged DNA from ever dividing and hence inducing cancer or other deleterious biologic outcomes. (Reproduced with permission from Blanpain C, Mohrin M, Sotiropoulou PA, et al: DNA-damage response in tissue-specific and cancer stem cells. Cell Stem Cell. 2011;8(1):16-29.)

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مواضيع ذات صلة

RNA is Synthesized From A DNA Template by RNA Polymerases

DNA & Chromosome Integrity Is Monitored Throughout the Cell Cycle

Micro-RNA and Long Noncoding RNA

Histone Organization

Noncoding DNA

DNA Synthesis Occurs During the S Phase of the Cell Cycle

Formation of Replication Bubbles

Initiation & Elongation of DNA Synthesis

The Exact Function of Much of the Mammalian Genome is Not Well Understood

DNA is organized into Chromosomes

Some Regions of Chromatin are “Active” & Others are “Inactive”

The Nucleosome Contains Histone & DNA