Checkpoint controls

Peng CY, Graves PR, Thoma RS, Wu Z, Shaw AS, Piwnica-Worms H 1997 Mitotic and G2 checkpoint control regulation of 14-3-3 protein binding by phosphorylation of Cdc25C on serine-216. Science 277 1501—1505... 

Hartwell LH, Weinert TA 1989 Checkpoints controls that ensure the order of cell cycle events. Science 246 629-634... 

Murray and Hunt, 1993). Cyclins, kinases, and phosphatases that regulate the passage of the cell through the G] — S phase transition are all present in mammals, invertebrates, and plants (Solomon, 1993 Doonan and Fobart, 1997 Zavitz and Zipursky, 1997). However, multicellular eukaryotes contain multiple orthologs of yeast cell cycle proteins they initiate proliferation via growth factors, rather than, for example, yeast mating factors, and they possess additional checkpoint controls and repair pathways. 

Moreover, the CSN is involved in checkpoint control. The double deletions of csnl and csn2 mutants crossed with checkpoint pathway mutants such as rad3, chk, and cdsl are synthetically lethal in S. pombe [52]. Cdsl kinase is constitutively activated in csnl mutants. Similarly, loss of csn5 in Drosophila results in activation of Mei-41, one of the ATM/ATR family kinases involved in meiotic checkpoint upon DNA damage [90]. 

Boisvert, F.M., Dery U., Masson, J.Y. and Richard, S. (2005) Arginine methylation of MREll by PRMTl is required for DNA damage checkpoint control. Genes and Development, 19, 671-676. 

The metaphase-anaphase checkpoint controls the formation of the spindle apparatus and the correct alignment of chromosomes, and may initiate metaphase arrest (see Chapter 13). On failure of the control system, the occmrence of abnormal chromosomes is favored. In various cancer cells, chromosomal instabUity is associated with loss of function of the BUBl gene, which is part of the metaphase-anaphase checkpoint (Cahill et al., 1998). 

Wang X, Jin DY, Ng RW et al. Significance of MAD2 expression to mitotic checkpoint control in ovarian cancer cells. Cancer Res 2002 62 1662-1668. 

Clearly, this complex process must be controlled by the cell such that there are checkpoint controls, which make sure that there are two centrosomes and two half spindles, that the correct chromatids associate with the correct half-spindle and that separation does not occur until all of the chromatids are in the correct place. Failure of any part of this system could lead to the wrong number of chromosomes in one daughter cell. This uneven segregation is known as chromosomal nondisjunction. A number of chemicals, including some drugs, will interfere with this process. Thus, spindle formation can be disrupted, so the chromosomes may segregate in a random fashion. 

Margeta-Mitrovic M, Jan YN, Jan LY (2000) A trafficking checkpoint controls GABAb receptor heterodimerization. Neuron 27 97-106... 

Stevens C, La Thangue NB. 2004. The emerging role of E2F-1 in the DNA damage response and checkpoint control. DNA... 

DNA repair is the major cellular defense system against DNA damage, which physically removes the lesions from DNA. Cell cycle checkpoint control empowers the repair system with better efficiency in that the cell cycle is temporarily halted to allow more time for DNA repair. In multicell organisms, apoptosis is additionally employed to remove excessively damaged cells. Nevertheless, these cellular defense... 

Fig. 12.1 The phases between the end and the start of mitosis are the interphases. Gi and G2- In clockwise direction, between the end of Gi and the start of G2 comes the S-phase, when DNA is synthesized and replicated. After mitosis cells may enter a quiescent phase, Gq, or proceed to Gi and eventually to the S-phase. Checkpoint controls sense DNA damage and arrest the cell cycle in either Gi or G2. These controls prevent DNA synthesis and replication and mitosis, either when DNA is damaged or when DNA has not been properly replicated.

As example of a checkpoint control, the response of the cell cycle in yeast to DNA damage will be described. Damaged DNA activates a checkpoint kinase (chkl) which is targeted to... 

Because of its role in cell-cycle control and proliferation, pRB is an attractive target for agents designed to enforce cell-cycle checkpoint controls that block malignant transformation. 

There are checkpoints controlling replication and separation of chromosomes during mitosis. A DNA-damage checlqjoint controls chromosome replication and stops cells... 

When the checkpoint control has sensed a defect in the micotubular attachments, the cell is arrested in metaphase. Mutants of the human hBUBl gene have been detected... 

Rg. 17.1 The mitotic-spindle checkpoints ensure that chromosomes are aligried correctly before anaphase. If chromosomes are not attached stably to the microtubules, the checkpoint control prevents entry into anaphase, the irreversible step in cell division. ... 

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