Protein kinase replication complex

The activity of the S phase cyclin-CDK complex is, in turn, controlled by an inhibitor, the Sicl protein. At the start of G1 phase, the S phase cyclin-CDK complex is inactivated by the Sic-1 protein. Only when the inhibitor is degraded by ubiquitin-media-ted proteolysis when the start point is crossed is an active S phase cyclin-CDK complex available. This removes the MCM proteins and Cdc6 protein from the origin by phos-phorylating them and thus enables replication. A second protein kinase, Cdc7/Dbf4p complex, is also involved in this phosphorylation. Once replication has taken place, the renewed formation of a pre-RC is hindered by the activity of the G2/M cyclin-CDK complex. 

The increase in nuclear cyclin B/CDKl activity promotes phosphorylation of nuclear substrates that are necessary for mitosis, such as nuclear envelope breakdown, spindle formation, chromatin condensation, and restmcturing of the Golgi and endoplasmic reticulum (85, 86). Numerous cyclin B/CDKl substrates have been dehned, which include nuclear lamins, nucleolar proteins, centrosomal proteins, components of the nuclear pore complex, and microtubule-associated proteins (87-89). Cyclin B/CDKl complexes also phosphorylate MCM4 to block replication of DNA, the TFIIH subunit of RNA polymerase II to inhibit transcription, and the ribosomal S6 protein kinase to prevent translation during mitosis (90-92). 

The association of ATR with replication forks is thought to activate its protein kinase activity, leading to the phosphorylation and activation of the Chkl kinase. Active Chkl then phosphorylates and inactivates the Cdc25 phosphatase (Cdc25C in vertebrates), which normally removes the inhibitory phosphate from CDKs that function during mitosis. As a result, the cyclln A/B-CDKl complexes remain inhibited and cannot phosphorylate targets required to initiate mitosis. ATR continues to initiate this protein kinase cascade until all replication forks complete DNA replication and disassemble. 

The activation of protein kinase C and subsequent induction of cell proliferation by cytotoxic chemicals has been suggested by Roghani et al. (64). The inappropriate activation of this enzyme by a chemical-receptor complex is believed to play a role in the promotion process. The activation of protein kinase C may subsequently result in the activation of a number of cytoplasmic proteins through inductional phosphorylation and set off a chain of events which includes enhanced cell proliferation in the absence of regenerative cell replication. The distinction between cytotoxicity and promotion may not always be clear. As recently discussed by Trump and Berezesky (65), chemically-induced alterations in the cellular dynamics of calcium regulation may result in a wide range of changes, many of which are similar to those caused by protein kinase C... 

BER, base excision repair DNA-PK, DNA-dependent protein kinase DSB, double strand break MNNG, N-methyl-N -nitro-N-nitrosoguanidine MRC, multiprotein DNA replication complex NER, nucleotide excision repair PAR, poly(ADP-ribose) PARP-1, poly(ADP-ribose) pol)mierase-l PCNA, proliferatii cell nuclear ant en p21, p21 pol 5, DNA pol)mierase 5 SSB, single strand break WRN, Werner syndrome protein. 

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