The MCAT (Medical College Admission Test) is offered by the AAMC and is a required exam for admission to medical schools in the USA and Canada. Correspondingly, HR is largely inhibited while cells are in the G1 phase of the cell cycle, when the sister chromatid has not yet been replicated.Welcome to the BEST place for MCAT prep and practice materials. In somatic cells, HR predominantly uses the sister chromatid as a template for DSB repair, rather than the homologous chromosome. As expected, HR is extremely accurate, as it leads to precise repair of the damaged locus using DNA sequences homologous to the broken ends. In contrast to NHEJ, homologous recombination (HR) requires a homologous DNA sequence to serve as a template for DNA-synthesis-dependent repair and involves extensive DNA-end processing. However, during the process of NHEJ, insertions or deletions within the joined regions may occur. NHEJ protects genetic integrity by rejoining broken strands of DNA that may otherwise be lost during DNA replication and cell regeneration. Although being active throughout the cell cycle, NHEJ is relatively more important during G1 phase. Repair by NHEJ involves direct resealing of the two broken ends independently of sequence homology. NHEJ repair is the simplest and most widely utilized mechanism to repair DSB that occur in DNA. NHEJ and HR are regulated based on the cell cycle.įigure 2: Non-homologous end-joining (NHEJ) The G1 and G2 phases are critical regulatory checkpoints, whereby the restriction point between the G1 and S phase determines whether the cells enter the S phase or exit the cell cycle to halt at the G0 phase.įigure 1: The cell cycle is controlled at three checkpoints. Integrity of the DNA is assessed at the G 1 checkpoint. Proper chromosome duplication is assessed at the G 2 checkpoint. Attachment of each kinetochore to a spindle fiber is assessed at the M checkpoint.Ĭells have evolved two main mechanisms to repair double-strand breaks within the DNA: the non-homologous end-joining (NHEJ)( Figure 2), that ensures direct resealing of DNA ends and the homologous recombination (HR) ( Figure 3) that relies on the presence of homologous DNA sequences for DSB repair. Multiple checkpoints exist within each stage of the cell cycle to ensure the faithful replication of DNA in the S phase and the precise separation of the chromosomes into daughter cells. The cell cycle consists of four distinct and ordered phases, termed G0/G1 (gap 1), S (DNA synthesis), G2 (gap 2), and M (mitosis). The cell cycle process is highly conserved and precisely controlled to govern the genome duplication and separation into the daughter cells. In multicellular organisms, the response to DNA damage can result in two major physiological consequences: (1) Cells can undergo cell cycle arrest, repair the damage and re-enter the cell cycle, or (2) cells can be targeted for cell death (apoptosis) and removed from the population. The sensor phase recognizes the damage and activates the signal transduction phase to block cell cycle progression and select the appropriate repair pathway. Within cells, multiple pathways contribute to DNA repair, but independent of the specific repair pathway involved, three phases of checkpoint activation are traditionally identified: (1) Sensing of damage, (2) Activating the signaling cascade, and (3) Switching on downstream effectors. Once the damaged DNA is repaired, the checkpoint machinery triggers signals that will resume cell cycle progression. Checkpoints are induced to delay cell cycle progression and to allow cells time to repair damaged DNA prior to DNA replication. DNA damage checkpoints have been functionally conserved throughout eukaryotic evolution, with most of the relevant players in the checkpoint response highly conserved from yeast to humans. However, regardless of the type of damage a sophisticated surveillance mechanism, that elicits DNA damage checkpoints, detects and signals its presence to the DNA repair machinery. To preserve genome integrity, eukaryotic cells have evolved repair mechanisms specific for different types of DNA Damage. Genetic damage produced by either exogenous or endogenous mechanisms represents an ongoing threat to the cell. As described in this section, the cell cycle checkpoint has another critical function in response to cellular stress and DNA damage. In the previous section, we learn how the cell cycle checkpoint allows timely progression of the cell cycle in undamaged cells.
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