MCAT Biochemistry
DNA repair mechanisms involve a series of enzyme-driven events that recognize and fix damaged or mispaired DNA to prevent the accumulation of mutations that can lead to clinical problems, such as cancer. The three pathways for single-strand DNA repair are nucleotide excision repair (NER), base excision repair (BER), and mismatch repair (MMR). NER is responsible for removing bulky-helix lesions caused by UV radiation, in a process involving helicase, endonuclease, DNA polymerase, and ligase. BER focuses on fixing deaminated, oxidized, and alkylated base lesions, with glycosylase, AP endonuclease, AP lyase, DNA polymerase, and ligase playing key roles. MMR, on the other hand, detects and replaces mispaired bases that form during DNA replication.
For double-strand DNA repair, there are two pathways: non-homologous end joining (NHEJ) and homologous recombination (HR). NHEJ connects the broken ends of double-stranded DNA without using a template, leading to a higher likelihood of errors. In contrast, HR utilizes the complementary strand of the undamaged homologous chromosome as a template, making it a more accurate process. Furthermore, HR promotes genetic variation in offspring by mixing genetic material during meiosis.
Lesson Outline
<ul> <li>Single strand repair mechanisms:</li> <ul> <li>Nucleotide excision repair (NER):</li> <ul> <li>Step 1: Helicase unwinds the damaged DNA</li> <li>Step 2: Endonuclease removes the damaged nucleotides</li> <li>Step 3: DNA polymerase fills the gap</li> <li>Step 4: Ligase seals the gap</li> </ul> <li>Base excision repair (BER):</li> <ul> <li>Step 1: Glycosylase removes the base lesion</li> <li>Step 2: AP endonuclease and AP lyase make nicks in the strand</li> <li>Step 3: DNA polymerase fills the gap</li> <li>Step 4: Ligase seals the nick</li> </ul> <li>Mismatch repair (MMR):</li> <ul> <li>Step 1: Mismatch repair enzymes identify the mispaired base</li> <li>Step 2: Endonuclease removes the mispaired base</li> <li>Step 3: DNA polymerase fills the gap</li> <li>Step 4: Ligase seals the gap</li> </ul> </ul> <li>Double strand repair mechanisms:</li> <ul> <li>Nonhomologous end joining (NHEJ):</li> <ul> <li>Process of attaching broken ends of double stranded DNA without a template</li> </ul> <li>Homologous recombination (HR):</li> <ul> <li>Higher accuracy repair by using a template to fix double stranded DNA breaks</li> <li>Promotes genetic variation in offspring</li> </ul> </ul> <li>Clinical pearls and genetic disorders:</li> <ul> <li>Xeroderma pigmentosum (NER-related)</li> <li>Lynch syndrome (MMR-related)</li> <li>Ataxia-telangiectasia (NHEJ-related)</li> <li>Hereditary breast/ovarian cancer syndrome & Fanconi anemia (HR-related)</li> </ul> </ul>
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FAQs
Nucleotide excision repair (NER) and base excision repair (BER) are both DNA repair mechanisms that correct damaged DNA, but they differ in their methods and the types of damage they address. NER is responsible for repairing bulky adducts and lesions, such as those caused by UV light, by removing an entire region of the damaged DNA and replacing it. BER, on the other hand, corrects small base modifications, such as deamination and alkylation, by removing and replacing only the damaged base itself.
Mismatch repair (MMR) is a mechanism that corrects base-pair mismatches and insertion/deletion loops that occur during DNA replication. These errors, if left unrepaired, can cause an increased risk of cancer and contribute to Lynch syndrome, a hereditary condition characterized by a higher risk of developing colorectal and other cancers. By maintaining the fidelity of DNA replication, MMR prevents the accumulation of mutations within the genome, thereby mitigating the risk factors associated with Lynch syndrome.
Nonhomologous end joining (NHEJ) and homologous recombination (HR) are two DNA repair mechanisms that address double-strand breaks (DSBs) in DNA. NHEJ repairs DSBs by directly ligating the ends of the broken DNA strands without using a homologous template. This can result in insertions or deletions, making NHEJ an error-prone repair mechanism. In contrast, HR is a more accurate repair method that uses a homologous template, typically a sister chromatid, to accurately repair the broken ends. HR is mostly active during the S and G2 phases of the cell cycle, when a sister chromatid is available.
Xeroderma pigmentosum (XP) is a rare genetic disorder caused by defects in the nucleotide excision repair (NER) mechanism. Individuals with XP have a reduced ability to repair DNA damage caused by UV radiation from the sun, which results in an increased risk of developing skin cancers and other symptoms, such as extreme sensitivity to sunlight, freckling, and neurological disorders. The dysfunction of NER in XP patients highlights the importance of this repair mechanism in preventing mutagenesis and maintaining genomic stability.
A BRCA-1 mutation can result in a dysfunctional or absent BRCA-1 protein, which plays a crucial role in homologous recombination (HR)-mediated repair of DNA double-strand breaks. Impairment of this repair mechanism increases the likelihood of error-prone repair pathways, such as nonhomologous end joining, which can result in chromosomal rearrangements and the accumulation of other genetic mutations. This can ultimately increase an individual's risk of developing breast, ovarian, and other cancers. Carriers of BRCA-1 mutations often have a significantly higher lifetime risk of developing these cancers compared to the general population.
