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Many research programs focused on understanding the mechanism of action of the internal S -phase checkpoint , which oversees both the processes associated with the frequency of initiation of DNA replication (density regions of origin ) and with the replication fork movement ( elongation rate ) . Replication rate decreases in response to hydroxyurea , aphidicolin or DNA damaging agents . Decreased rate of replication is due to activate the biochemical pathways related to internal control point of the internal function of the S phase of the S phase checkpoint are : ( 1 ) slowing the rate of or prevent replication fork movement , ( 2 ) preventing the premature start late origin , ( 3 ) initiating signaling pathways associated with the response to the occurrence of structural defects in DNA , in order to prevent replication of damaged DNA molecules , and ( 4 ) delaying entry into mitosis until no stress stimulus . The study presents the latest information on protein kinases ATR , ATM , Chk1 and Chk2 are involved in the control of S phase , describe the current state of knowledge about the other proteins involved in reactions associated with response to replication stress and additionally attempt to clarify their mutual correlation . Protein kinases ATM and ATR kinases belong to a family of 3- phosphatidylinositol . Despite demonstrating significant role that ATM and ATR kinases in signaling pathways of the cell cycle , still little is known about the mechanisms of activation of these kinases. Phosphorylated kinases ATM and ATR activate the subordinate target proteins ( kinase Chk2 and Chk1 ) through its phosphorylation on serine and threonine residues . DNA double-strand breaks activates the ATM kinase that phosphorylates the N-terminal kinase subordinate Chk2 ( Thr68 ) . Threonine phosphorylation is a prerequisite 68 to fully activate the Chk2 kinase , which is assigned to the autophosphorylation of the process , carried out at 383 and 387 treoninach ATR kinase is activated in response to stress or DNA replication induced DNA damage by UV radiation . When activated , it shall Chk1 kinase phosphorylation on serine residues : Ser317 and Ser345 . Phosphorylation of serine 345 enhances the Chk1 kinase quickly locate the area of ​​the cell nucleus during checkpoint activation . Serine phosphorylation state transitions to block 317 ensures S ? G2 and prevents entering mitosis , run under conditions of compromised DNA replication . In some situations, the conditioned stimulus acting kind of stress kinases ATM and ATR ensoryczne can phosphorylate a common target proteins . Chk1 kinase phosphorylated calls aktywująco phosphate groups fosfatazom protein cdc25 -C , which leads to block kinases Cdk1 and Cdk2 and consequently to halt cell cycle progression . Chk1 kinase may also stabilize the replication fork , possibly through targeting of proteins Cdc6 and MCM2 -7 and - for the relief of the stress stimulus - re- run them . Functional variability of proteins forming the molecular axis ATM/ATR-Chk2/Chk1-Cdc25/Cdk is the foundation of internal S -phase checkpoint kinase ATR substrate subordinate is also histone H2AX phosphorylated at serine 139 after the occurrence of DNA DSBs damage type , number of particles histone H2AX phosphorylated on Ser139 , are collected in damage , forming intranuclear foci . Most of fluorescing foci are distributed throughout the nucleoplasm area , but most of them are usually associated with areas of heterochromatin okołojąderkowej . Phosphorylated histone H2AX form a platform through which to places redirected damage repair factors and signaling proteins . The article also describes the consequences of breaking the internal function of the S phase checkpoint and avoid depending SM and the consequent induction of premature chromosome condensation . In addition to numerous mutations that eliminate the individual components of a biochemical pathway related to the internal S phase checkpoint , the system can also be disturbed by the impact of many chemical . These include caffeine , which breaks the dependency SM and leads to the induction of PCC in these cells , which are not prepared for entry into mitosis , because of the failure to the S phase and repair processes poreplikacyjnych G2 phase . Cells were blocked in the course of the S phase , and then treated with caffeine , initiate aberrant mitotic divisions . In such cells, we observe the occurrence of voids and gaps in the continuity of chromosomes , the loss in the equatorial plane acentrycznych chromosomes and chromatid fragments and the formation of chromosome bridges and micronuclei . It follows from this new understanding of the internal functions of the S -phase checkpoint : as closely affecting the subsequent formation of higher order structures : metaphase chromosomes , thereby ensuring the separation of DNA equally acceptable to two sister nuclei . The phenomenon of premature mitosis is not only a significant problem the basic biology of the cell cycle , but also an important issue because of the potential medical applications . Methods of radio - and chemotherapy used in the treatment of neoplastic diseases lead to extensive damage DNA replication abstained genetic material. According to many scientists , increased therapeutic effects may result from stimulation of the biochemical mechanisms that bypassing the internal operation of the S phase checkpoint , would induce premature chromosome condensation .

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The Editorial Board
Andrzej Łukaszyk - przewodniczący, Zofia Bielańska-Osuchowska, Szczepan Biliński, Mieczysław Chorąży, Aleksander Koj, Włodzimierz Korochoda, Leszek Kuźnicki, Aleksandra Stojałowska, Lech Wojtczak

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Katedra i Zakład Histologii i Embriologii Uniwersytetu Medycznego w Poznaniu, ul. Święcickiego 6, 60-781 Poznań, tel. +48 61 8546453, fax. +48 61 8546440, email: mnowicki@ump.edu.pl

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