Chapter15_SSM - 65781_CH15_293_309.qxd 8/1/08 1:21 PM Page...

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Chapter 15: Molecular Genetics of the Cell Cycle and Cancer Chapter Summary The essential function of the cell cycle is to ensure that each chromosomal DNA molecule is replicated once in the cell cycle and that the genetically identical daughter chromosomes are distributed equally to daughter cells. The cell cycle comprises four phases: G 1 (gap/growth 1), S (DNA synthesis), G 2 (gap/growth 2), and M (mitosis). Key events in the cycle that ensure proper replication and segregation of chromosomes include centrosome duplication and positioning, replication of the DNA, formation of the bipolar spindle, attachment of each centromere to spindle fibers from each pole, proper functioning of the spindle, and disjunction of the chromosomes. The cell cycle has been studied genetically in both budding and fission yeast. Conditional mutants defective in the cell division cycle ( cdc mutants) arrest at particular places in the cell cycle under restrictive condi- tions. Arrest of the cell cycle in cdc mutants takes place at a limited number of points, which correspond to the position of checkpoints within the cell cycle. Progression from one stage of the cell cycle to the next is controlled by protein complexes called cyclin- dependent kinase (CDK) complexes. These are made up of a cyclin component, which is stage-specific, and a cyclin-dependent protein kinase. The CDK complexes phosphorylate stage-specific protein substrates to change their properties and thus make possible particular reaction sequences. Cyclins are synthesized immediately prior to their use and degraded immediately thereafter. Prior to the G 1 /S transition in animal cells, the cyclin–CDKs phosphorylate the retinoblastoma protein, RB, which changes its conformation and thereby frees the E2F transcription factor, which until this time is ren- dered inactive by binding with RB. The free E2F activates transcription of enzymes needed for synthesis of DNA. The event responsible for the onset of S phase is phosphorylation of one or more proteins in the protein complex assembled at the origins of replication, and DNA replication ensues. The G 2 /M transition involves phosphorylation of cyclin B, resulting in its retention in the nucleus. Cyclin B–CDK phosphorylates proteins required for assembly of the spindle and dissolution of the nuclear 293
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294 membrane. The onset of anaphase and the exit from mitosis are controlled by proteolysis via activity of the anaphase-promoting complex (APC). Proteolysis ensures that sister chromatids separate and that cyclin B is degraded, propelling the cell into the next G 1 phase. Cells monitor external and internal conditions. If defects are detected, checkpoint mechanisms halt cell- cycle progression, allowing time for repair or correction. Major checkpoints monitor the DNA in G 1 and S, duplication of the centrosome, and attachment of chromosomes to the spindle. In animal cells, DNA damage activates a signal transduction pathway that results in phosphorylation and
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This note was uploaded on 09/29/2011 for the course GENETICS 380 taught by Professor Glodowski during the Spring '08 term at Rutgers.

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Chapter15_SSM - 65781_CH15_293_309.qxd 8/1/08 1:21 PM Page...

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