Safeguarding genome integrity: the checkpoint kinases ATR, CHK1 and WEE1 restrain CDK activity during normal DNA replication
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Safeguarding genome integrity : the checkpoint kinases ATR, CHK1 and WEE1 restrain CDK activity during normal DNA replication. / Sørensen, Claus Storgaard; Syljuåsen, Randi G.
I: Nucleic Acids Research, Bind 40, Nr. 2, 2012, s. 477-86.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Safeguarding genome integrity
T2 - the checkpoint kinases ATR, CHK1 and WEE1 restrain CDK activity during normal DNA replication
AU - Sørensen, Claus Storgaard
AU - Syljuåsen, Randi G
PY - 2012
Y1 - 2012
N2 - Mechanisms that preserve genome integrity are highly important during the normal life cycle of human cells. Loss of genome protective mechanisms can lead to the development of diseases such as cancer. Checkpoint kinases function in the cellular surveillance pathways that help cells to cope with DNA damage. Importantly, the checkpoint kinases ATR, CHK1 and WEE1 are not only activated in response to exogenous DNA damaging agents, but are active during normal S phase progression. Here, we review recent evidence that these checkpoint kinases are critical to avoid deleterious DNA breakage during DNA replication in normal, unperturbed cell cycle. Possible mechanisms how loss of these checkpoint kinases may cause DNA damage in S phase are discussed. We propose that the majority of DNA damage is induced as a consequence of deregulated CDK activity that forces unscheduled initiation of DNA replication. This could generate structures that are cleaved by DNA endonucleases leading to the formation of DNA double-strand breaks. Finally, we discuss how these S phase effects may impact on our understanding of cancer development following disruption of these checkpoint kinases, as well as on the potential of these kinases as targets for cancer treatment.
AB - Mechanisms that preserve genome integrity are highly important during the normal life cycle of human cells. Loss of genome protective mechanisms can lead to the development of diseases such as cancer. Checkpoint kinases function in the cellular surveillance pathways that help cells to cope with DNA damage. Importantly, the checkpoint kinases ATR, CHK1 and WEE1 are not only activated in response to exogenous DNA damaging agents, but are active during normal S phase progression. Here, we review recent evidence that these checkpoint kinases are critical to avoid deleterious DNA breakage during DNA replication in normal, unperturbed cell cycle. Possible mechanisms how loss of these checkpoint kinases may cause DNA damage in S phase are discussed. We propose that the majority of DNA damage is induced as a consequence of deregulated CDK activity that forces unscheduled initiation of DNA replication. This could generate structures that are cleaved by DNA endonucleases leading to the formation of DNA double-strand breaks. Finally, we discuss how these S phase effects may impact on our understanding of cancer development following disruption of these checkpoint kinases, as well as on the potential of these kinases as targets for cancer treatment.
KW - Animals
KW - Cell Cycle Proteins
KW - Cell Transformation, Neoplastic
KW - Cyclin-Dependent Kinases
KW - DNA Damage
KW - DNA Replication
KW - Genome
KW - Humans
KW - Mice
KW - Nuclear Proteins
KW - Protein Kinases
KW - Protein-Serine-Threonine Kinases
KW - Protein-Tyrosine Kinases
U2 - 10.1093/nar/gkr697
DO - 10.1093/nar/gkr697
M3 - Journal article
C2 - 21937510
VL - 40
SP - 477
EP - 486
JO - Nucleic Acids Research
JF - Nucleic Acids Research
SN - 0305-1048
IS - 2
ER -
ID: 40794618