Given the importance of normal DNA and chromosome function to survival and propagation, it is not surprising that eukaryotic cells have developed elaborate mechanisms to monitor the integrity of the genetic material. As detailed earlier, a number of complex multisubunit enzyme systems have evolved to repair damaged DNA at the nucleotide sequence level. Similarly, DNA mishaps at the chromosome level are also monitored and repaired. As shown in Figure 1, both DNA and chromosomal integrity are continuously monitored throughout the cell cycle. The four specific steps at which this monitoring occurs have been termed checkpoint controls. If problems are detected at any of these checkpoints, progression through the cycle is interrupted and transit through the cell cycle is halted until the damage is repaired. The molecular mechanisms underlying detection of DNA damage during the G1 andG2 phases of the cycle are understood better than those operative during S and M phases.

Fig1. Progress through the mammalian cell cycle is continuously monitored via multiple cell-cycle checkpoints. DNA, chromosome, and chromosome segregation integrity are continuously monitored throughout the cell cycle. If DNA damage is detected in either the G1 or the G2 phase of the cell cycle, if the genome is incompletely replicated, or if normal chromosome segregation machinery is incomplete (ie, a defective spindle), cells will not progress through the phase of the cycle in which defects are detected. In some cases, if the damage cannot be repaired, such cells undergo programmed cell death (apoptosis). Note that cells can reversibly leave the cell cycle during G1 entering a nonreplicative state termedG0. When appropriate signals/conditions occur, cells reenter G1 and progress normally through the cell cycle as depicted.

The tumor suppressor p53, a protein of apparent MW 53 kDa on SDS-PAGE, plays a key role in both G1 and G2 checkpoint control. Normally a very unstable protein, p53 is a DNA-binding transcription factor, one of a family of related proteins (ie, p53, p63, and p73) that is stabilized in response to DNA damage, perhaps by direct p53-DNA interactions. Like the histones discussed earlier, p53 is subject to a panoply of regulatory PTMs, all of which likely modify its multiple biologic activities. Increased levels of p53 activate transcription of an ensemble of genes that collectively serve to delay transit through the cycle. One of these induced proteins, p21, is a potent CDK–cyclin inhibitor (CKI) that is capable of efficiently inhibiting the action of all CDKs. Clearly, inhibition of CDKs will halt progression through the cell cycle (see Figures 1 and 2). If DNA damage is too extensive to repair, the affected cells undergo apoptosis (programmed cell death) in a p53-dependent fashion. In this case, p53 induces the activation of a collection of genes that induce apoptosis. Cells lacking functional p53 fail to undergo apoptosis in response to high levels of radiation or DNA-active chemotherapeutic agents. It may come as no surprise, then, that p53 is one of the most frequently mutated genes in human cancers. Indeed, recent genomic sequencing studies of a multitude of tumor DNA samples suggest that over 80% of human cancers carry p53 loss-of-function mutations. Additional research into the mechanisms of checkpoint control will prove invaluable for the development of effective anti-cancer therapeutic options.

Fig2. Schematic illustration of the points during the mammalian cell cycle during which the indicated cyclins and cyclin-dependent kinases are activated. The thickness of the various colored lines is indicative of the extent of activity.

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مواضيع ذات صلة

RNA is Synthesized From A DNA Template by RNA Polymerases

All Organisms Contain Elaborate Evolutionarily Conserved Mechanisms to Repair Damaged DNA

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