Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Aven-dependent activation of ATM following DNA damage.
Guo JY, Yamada A, Kajino T, Wu JQ, Tang W, Freel CD, Feng J, Chau BN, Wang MZ, Margolis SS, Yoo HY, Wang XF, Dunphy WG, Irusta PM, Hardwick JM, Kornbluth S.
???displayArticle.abstract???
In response to DNA damage, cells undergo either cell-cycle arrest or apoptosis, depending on the extent of damage and the cell's capacity for DNA repair. Cell-cycle arrest induced by double-stranded DNA breaks depends on activation of the ataxia-telangiectasia (ATM) protein kinase, which phosphorylates cell-cycle effectors such as Chk2 and p53 to inhibit cell-cycle progression. ATM is recruited to double-stranded DNA breaks by a complex of sensor proteins, including Mre11/Rad50/Nbs1, resulting in autophosphorylation, monomerization, and activation of ATM kinase. In characterizing Aven protein, a previously reported apoptotic inhibitor, we have found that Aven can function as an ATM activator to inhibit G2/M progression. Aven bound to ATM and Aven overexpressed in cycling Xenopus egg extracts prevented mitotic entry and induced phosphorylation of ATM and its substrates. Immunodepletion of endogenous Aven allowed mitotic entry even in the presence of damaged DNA, and RNAi-mediated knockdown of Aven in human cells prevented autophosphorylation of ATM at an activating site (S1981) in response to DNA damage. Interestingly, Aven is also a substrate of the ATM kinase. Mutation of ATM-mediated phosphorylation sites on Aven reduced its ability to activate ATM, suggesting that Aven activation of ATM after DNA damage is enhanced by ATM-mediated Aven phosphorylation. These results identify Aven as a new ATM activator and describe a positive feedback loop operating between Aven and ATM. In aggregate, these findings place Aven, a known apoptotic inhibitor, as a critical transducer of the DNA-damage signal.
Abraham,
Cell cycle checkpoint signaling through the ATM and ATR kinases.
2001, Pubmed
Abraham,
Cell cycle checkpoint signaling through the ATM and ATR kinases.
2001,
Pubmed Ahn,
Threonine 68 phosphorylation by ataxia telangiectasia mutated is required for efficient activation of Chk2 in response to ionizing radiation.
2000,
Pubmed Ali,
Requirement of protein phosphatase 5 in DNA-damage-induced ATM activation.
2004,
Pubmed Bakkenist,
DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation.
2003,
Pubmed Bakkenist,
Initiating cellular stress responses.
2004,
Pubmed Bartkova,
ATM activation in normal human tissues and testicular cancer.
2005,
Pubmed Bratton,
Recruitment, activation and retention of caspases-9 and -3 by Apaf-1 apoptosome and associated XIAP complexes.
2001,
Pubmed Chaturvedi,
Mammalian Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway.
1999,
Pubmed Chau,
Aven, a novel inhibitor of caspase activation, binds Bcl-xL and Apaf-1.
2000,
Pubmed Choi,
Aven overexpression: association with poor prognosis in childhood acute lymphoblastic leukemia.
2006,
Pubmed Coleman,
Negative regulation of the wee1 protein kinase by direct action of the nim1/cdr1 mitotic inducer.
1993,
Pubmed Coleman,
Cdc2 regulatory factors.
1994,
Pubmed Deming,
Study of apoptosis in vitro using the Xenopus egg extract reconstitution system.
2006,
Pubmed
,
Xenbase Figueroa,
Aven and Bcl-xL enhance protection against apoptosis for mammalian cells exposed to various culture conditions.
2004,
Pubmed Furnari,
Cdc25 inhibited in vivo and in vitro by checkpoint kinases Cds1 and Chk1.
1999,
Pubmed Furnari,
Cdc25 mitotic inducer targeted by chk1 DNA damage checkpoint kinase.
1997,
Pubmed Guo,
Response of Xenopus Cds1 in cell-free extracts to DNA templates with double-stranded ends.
2000,
Pubmed
,
Xenbase Harrison,
Surviving the breakup: the DNA damage checkpoint.
2006,
Pubmed Hoffmann,
Phosphorylation and activation of human cdc25-C by cdc2--cyclin B and its involvement in the self-amplification of MPF at mitosis.
1993,
Pubmed
,
Xenbase Hunt,
Maturation promoting factor, cyclin and the control of M-phase.
1989,
Pubmed Hutchison,
Periodic DNA synthesis in cell-free extracts of Xenopus eggs.
1987,
Pubmed
,
Xenbase Hutchison,
The control of DNA replication in a cell-free extract that recapitulates a basic cell cycle in vitro.
1988,
Pubmed
,
Xenbase Izumi,
Elimination of cdc2 phosphorylation sites in the cdc25 phosphatase blocks initiation of M-phase.
1993,
Pubmed
,
Xenbase Kornbluth,
Apoptosis in Xenopus egg extracts.
1997,
Pubmed
,
Xenbase Kumagai,
The Xenopus Chk1 protein kinase mediates a caffeine-sensitive pathway of checkpoint control in cell-free extracts.
1998,
Pubmed
,
Xenbase Kumagai,
Claspin, a novel protein required for the activation of Chk1 during a DNA replication checkpoint response in Xenopus egg extracts.
2000,
Pubmed
,
Xenbase Lavin,
ATM activation and DNA damage response.
2007,
Pubmed Lee,
Positive regulation of Wee1 by Chk1 and 14-3-3 proteins.
2001,
Pubmed
,
Xenbase Lew,
Regulatory roles of cyclin dependent kinase phosphorylation in cell cycle control.
1996,
Pubmed Liu,
Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint.
2000,
Pubmed Margolis,
A role for PP1 in the Cdc2/Cyclin B-mediated positive feedback activation of Cdc25.
2006,
Pubmed
,
Xenbase Margolis,
PP1 control of M phase entry exerted through 14-3-3-regulated Cdc25 dephosphorylation.
2003,
Pubmed
,
Xenbase Margolis,
Role for the PP2A/B56delta phosphatase in regulating 14-3-3 release from Cdc25 to control mitosis.
2006,
Pubmed
,
Xenbase Melchionna,
Threonine 68 is required for radiation-induced phosphorylation and activation of Cds1.
2000,
Pubmed Minshull,
Translation of cyclin mRNA is necessary for extracts of activated xenopus eggs to enter mitosis.
1989,
Pubmed
,
Xenbase Mueller,
Cell cycle regulation of a Xenopus Wee1-like kinase.
1995,
Pubmed
,
Xenbase Murray,
Cyclin synthesis drives the early embryonic cell cycle.
1989,
Pubmed
,
Xenbase Newmeyer,
Cell-free apoptosis in Xenopus egg extracts: inhibition by Bcl-2 and requirement for an organelle fraction enriched in mitochondria.
1994,
Pubmed
,
Xenbase Paydas,
Survivin and aven: two distinct antiapoptotic signals in acute leukemias.
2003,
Pubmed Peng,
Mitotic and G2 checkpoint control: regulation of 14-3-3 protein binding by phosphorylation of Cdc25C on serine-216.
1997,
Pubmed Perry,
Cdc25 and Wee1: analogous opposites?
2007,
Pubmed Petersen,
Protein phosphatase 2A antagonizes ATM and ATR in a Cdk2- and Cdc7-independent DNA damage checkpoint.
2006,
Pubmed
,
Xenbase Raleigh,
The G(2) DNA damage checkpoint targets both Wee1 and Cdc25.
2000,
Pubmed Shi,
Mechanical aspects of apoptosome assembly.
2006,
Pubmed Shreeram,
Wip1 phosphatase modulates ATM-dependent signaling pathways.
2006,
Pubmed Smythe,
Systems for the study of nuclear assembly, DNA replication, and nuclear breakdown in Xenopus laevis egg extracts.
1991,
Pubmed
,
Xenbase Stanford,
Changes in regulatory phosphorylation of Cdc25C Ser287 and Wee1 Ser549 during normal cell cycle progression and checkpoint arrests.
2005,
Pubmed
,
Xenbase Traven,
SQ/TQ cluster domains: concentrated ATM/ATR kinase phosphorylation site regions in DNA-damage-response proteins.
2005,
Pubmed Uziel,
Requirement of the MRN complex for ATM activation by DNA damage.
2003,
Pubmed Yoo,
Mcm2 is a direct substrate of ATM and ATR during DNA damage and DNA replication checkpoint responses.
2004,
Pubmed
,
Xenbase Zeng,
Replication checkpoint requires phosphorylation of the phosphatase Cdc25 by Cds1 or Chk1.
1998,
Pubmed Zermati,
Nonapoptotic role for Apaf-1 in the DNA damage checkpoint.
2007,
Pubmed
