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A dual role of Cdk2 in DNA damage response.

Satyanarayana A, Kaldis P - Cell Div (2009)

Bottom Line: Once it was believed that Cdk2 was the master regulator of S phase entry.Gene knockout mouse studies of cell cycle regulators revealed that Cdk2 is dispensable for S phase initiation and progression whereby Cdk1 can compensate for the loss of Cdk2.Whether these properties are unique to Cdk2 or also being compensated by other Cdks in the absence of Cdk2 is under extensive investigation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Molecular and Cell Biology (IMCB), Proteos, 61 Biopolis Drive, Singapore 138673, Republic of Singapore. satya@ncifcrf.gov.

ABSTRACT
Once it was believed that Cdk2 was the master regulator of S phase entry. Gene knockout mouse studies of cell cycle regulators revealed that Cdk2 is dispensable for S phase initiation and progression whereby Cdk1 can compensate for the loss of Cdk2. Nevertheless, recent evidence indicates that Cdk2 is involved in cell cycle independent functions such as DNA damage repair. Whether these properties are unique to Cdk2 or also being compensated by other Cdks in the absence of Cdk2 is under extensive investigation. Here we review the emerging new role of Cdk2 in DNA damage repair and also discuss how the loss of Cdk2 impacts the G1/S phase DNA damage checkpoint.

No MeSH data available.


Related in: MedlinePlus

Maintenance of the G1/S DNA damage checkpoint in the presence and absence of Cdk2. In response to DNA damage, activation of p53-p21 pathway is not altered in the absence of Cdk2, the primary target of p21 at the G1/S checkpoint. In the presence of Cdk2, the induced p21 inhibits Cdk2/cyclin E complexes in response to DNA damage. In the absence of Cdk2, Cdk1/cyclin E complexes are responsible for promotion of the G1/S transition and as a result become the target for p21 inhibition in response to DNA damage. Nevertheless, Cdk1 is not fully capable to rescue the functions of Cdk2 in DNA damage repair.
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Figure 1: Maintenance of the G1/S DNA damage checkpoint in the presence and absence of Cdk2. In response to DNA damage, activation of p53-p21 pathway is not altered in the absence of Cdk2, the primary target of p21 at the G1/S checkpoint. In the presence of Cdk2, the induced p21 inhibits Cdk2/cyclin E complexes in response to DNA damage. In the absence of Cdk2, Cdk1/cyclin E complexes are responsible for promotion of the G1/S transition and as a result become the target for p21 inhibition in response to DNA damage. Nevertheless, Cdk1 is not fully capable to rescue the functions of Cdk2 in DNA damage repair.

Mentions: The G1 cell cycle checkpoint is primarily responsible for preventing damaged DNA from being replicated. During G1/S DNA damage checkpoint arrest, ATM/ATR mediated activation of p53 activates one of its downstream targets, p21Cip1/Waf1 [17]. p21 binds to and inhibits Cdk2/cyclin E complexes thereby arresting cells at the G1/S transition. As a result, Cdk2 has become the prime target of the G1/S DNA damage checkpoint and Cdk2 inhibition by p21 is one essential step in maintaining the G1/S DNA damage checkpoint [12,17] (Figure 1). Nevertheless, the loss of Cdk2 presents a different challenge to cells, which in turn might lead to altered DNA damage response and checkpoint activation. An important issue that was ignored with regard to Cdk2's substitution by Cdk1 is how the G1/S DNA damage checkpoint functions in the absence of Cdk2. In this regard the first question that arises, is how the p53 pathway operates and how is p21 regulated in the absence of its target Cdk2? If p21 is induced and the cells arrest at the G1/S checkpoint, which target will be inhibited by p21 in the absence of Cdk2? In this context, the finding that Cdk1/cyclin E substitutes for Cdk2/cyclin E presents an interesting twist to the G1/S DNA damage checkpoint especially due to the fact that Cdk1 is the prime target for p21 at the G2/M DNA damage checkpoint [12,18]. In the absence of Cdk2, will Cdk1 be able to regulate both G1/S and G2/M DNA damage checkpoints? Or do the cells bypass the G1/S checkpoint in the absence of Cdk2 and arrest only at the G2/M checkpoint? If Cdk1 is able to maintain the G1/S checkpoint, will Cdk1 be inhibited by p21 or is it phosphorylated at the inhibitory sites Thr14/Tyr15 and restricted to the cytoplasm that occurs under certain circumstances during G2/M DNA damage checkpoint arrest? As a result it was of interest to reanalyze the translocation pattern of Cdk1 in response to DNA damage especially at the G1/S transition in the absence of Cdk2. Another important question is, if p21 would be able to arrest cells at the G1/S transition even in the absence of Cdk2, will this arrest be persistent enough for the cells to repair their damaged DNA and resume DNA replication?


A dual role of Cdk2 in DNA damage response.

Satyanarayana A, Kaldis P - Cell Div (2009)

Maintenance of the G1/S DNA damage checkpoint in the presence and absence of Cdk2. In response to DNA damage, activation of p53-p21 pathway is not altered in the absence of Cdk2, the primary target of p21 at the G1/S checkpoint. In the presence of Cdk2, the induced p21 inhibits Cdk2/cyclin E complexes in response to DNA damage. In the absence of Cdk2, Cdk1/cyclin E complexes are responsible for promotion of the G1/S transition and as a result become the target for p21 inhibition in response to DNA damage. Nevertheless, Cdk1 is not fully capable to rescue the functions of Cdk2 in DNA damage repair.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2690586&req=5

Figure 1: Maintenance of the G1/S DNA damage checkpoint in the presence and absence of Cdk2. In response to DNA damage, activation of p53-p21 pathway is not altered in the absence of Cdk2, the primary target of p21 at the G1/S checkpoint. In the presence of Cdk2, the induced p21 inhibits Cdk2/cyclin E complexes in response to DNA damage. In the absence of Cdk2, Cdk1/cyclin E complexes are responsible for promotion of the G1/S transition and as a result become the target for p21 inhibition in response to DNA damage. Nevertheless, Cdk1 is not fully capable to rescue the functions of Cdk2 in DNA damage repair.
Mentions: The G1 cell cycle checkpoint is primarily responsible for preventing damaged DNA from being replicated. During G1/S DNA damage checkpoint arrest, ATM/ATR mediated activation of p53 activates one of its downstream targets, p21Cip1/Waf1 [17]. p21 binds to and inhibits Cdk2/cyclin E complexes thereby arresting cells at the G1/S transition. As a result, Cdk2 has become the prime target of the G1/S DNA damage checkpoint and Cdk2 inhibition by p21 is one essential step in maintaining the G1/S DNA damage checkpoint [12,17] (Figure 1). Nevertheless, the loss of Cdk2 presents a different challenge to cells, which in turn might lead to altered DNA damage response and checkpoint activation. An important issue that was ignored with regard to Cdk2's substitution by Cdk1 is how the G1/S DNA damage checkpoint functions in the absence of Cdk2. In this regard the first question that arises, is how the p53 pathway operates and how is p21 regulated in the absence of its target Cdk2? If p21 is induced and the cells arrest at the G1/S checkpoint, which target will be inhibited by p21 in the absence of Cdk2? In this context, the finding that Cdk1/cyclin E substitutes for Cdk2/cyclin E presents an interesting twist to the G1/S DNA damage checkpoint especially due to the fact that Cdk1 is the prime target for p21 at the G2/M DNA damage checkpoint [12,18]. In the absence of Cdk2, will Cdk1 be able to regulate both G1/S and G2/M DNA damage checkpoints? Or do the cells bypass the G1/S checkpoint in the absence of Cdk2 and arrest only at the G2/M checkpoint? If Cdk1 is able to maintain the G1/S checkpoint, will Cdk1 be inhibited by p21 or is it phosphorylated at the inhibitory sites Thr14/Tyr15 and restricted to the cytoplasm that occurs under certain circumstances during G2/M DNA damage checkpoint arrest? As a result it was of interest to reanalyze the translocation pattern of Cdk1 in response to DNA damage especially at the G1/S transition in the absence of Cdk2. Another important question is, if p21 would be able to arrest cells at the G1/S transition even in the absence of Cdk2, will this arrest be persistent enough for the cells to repair their damaged DNA and resume DNA replication?

Bottom Line: Once it was believed that Cdk2 was the master regulator of S phase entry.Gene knockout mouse studies of cell cycle regulators revealed that Cdk2 is dispensable for S phase initiation and progression whereby Cdk1 can compensate for the loss of Cdk2.Whether these properties are unique to Cdk2 or also being compensated by other Cdks in the absence of Cdk2 is under extensive investigation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Molecular and Cell Biology (IMCB), Proteos, 61 Biopolis Drive, Singapore 138673, Republic of Singapore. satya@ncifcrf.gov.

ABSTRACT
Once it was believed that Cdk2 was the master regulator of S phase entry. Gene knockout mouse studies of cell cycle regulators revealed that Cdk2 is dispensable for S phase initiation and progression whereby Cdk1 can compensate for the loss of Cdk2. Nevertheless, recent evidence indicates that Cdk2 is involved in cell cycle independent functions such as DNA damage repair. Whether these properties are unique to Cdk2 or also being compensated by other Cdks in the absence of Cdk2 is under extensive investigation. Here we review the emerging new role of Cdk2 in DNA damage repair and also discuss how the loss of Cdk2 impacts the G1/S phase DNA damage checkpoint.

No MeSH data available.


Related in: MedlinePlus