A Proteomic Analysis of Ataxia Telangiectasia-mutated (ATM)/ATM-Rad3-related (ATR) Substrates Identifies the Ubiquitin-Proteasome System as a Regulator for DNA Damage Checkpoints

Mu, Jung-Jung; Wang, Yi; Luo, Hao; Leng, Mei; Zhang, Jinglan; Yang, Tao; Besusso, Dario; Jung, Sung Yun; Qin, Jun

doi:10.1074/jbc.c700079200

Cited by 169 publications

(146 citation statements)

References 32 publications

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“…MRE11, RAD50, and NBN are phosphorylated after DNA damage (46)(47)(48). In particular, after IR treatment, ATM phosphorylates NBN at Ser278 and Ser343 (21)(22)(23)(24).…”

Section: Discussionmentioning

confidence: 99%

Cleavage of the BRCT tandem domains of nibrin by the 657del5 mutation affects the DNA damage response less than the Arg215Trp mutation

et al. 2012

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SummaryThe Nijmegen breakage syndrome (NBS) is a genetic disorder caused by mutations in NBN gene and characterized by chromosomal instability and hypersensitivity to ionizing radiations (IR). The N-terminus of nibrin (NBN) contains a tandem breast cancer 1 (BRCA1) carboxy-terminal (BRCT) domain that represents one of the major mediators of phosphorylation-dependent protein-protein interactions in processes related to cell cycle checkpoint and DNA repair functions. Patients with NBS compound heterozygous for the 657del5 hypomorphic mutation and for the Arg215Trp missense mutation (corresponding to the 643C[T gene mutation) display a clinical phenotype more severe than that of patients homozygous for the 657del5 mutation. Here, we show that both the 657del5 and Arg215Trp mutations, occurring within the tandem BRCT domains of NBN, although not altering the assembly of the MRE11/RAD50/NBN (MRN) complex, affect the MRE11 IR-induced nuclear foci (IRIF) formation and the DNA doublestrand break (DSB) signaling via the phosphorylation of both ataxia-telangiectasia-mutated (ATM) kinase and ATM downstream targets (e.g., SMC1 and p53). Remarkably, data obtained indicate that the cleavage of the BRCT tandem domains of NBN by the 657del5 mutation affects the DNA damage response less than the Arg215Trp mutation. Indeed, the 70-kDa NBN fragment, arising from the 657del5 mutation, maintains the capability to interact with MRE11 and c-H2AX and to form IRIF. Altogether, the role of the tandem BRCT domains of NBN in the localization of the MRN complex at the DNA DSB and in the activation of the damage response is highlighted.

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“…MRE11, RAD50, and NBN are phosphorylated after DNA damage (46)(47)(48). In particular, after IR treatment, ATM phosphorylates NBN at Ser278 and Ser343 (21)(22)(23)(24).…”

Section: Discussionmentioning

confidence: 99%

Cleavage of the BRCT tandem domains of nibrin by the 657del5 mutation affects the DNA damage response less than the Arg215Trp mutation

et al. 2012

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“…We also generated point mutants of JCV TAg in which Glu at position 461 is replaced with Asp (E461D) or Ala (E461A); the corresponding mutants of SV40 TAg (residue 460) failed to bind nonspecifically to double-stranded DNA or ssDNA, respectively (39 -41). In addition, we constructed R541K of JCV TAg, the corresponding mutations of SV40 TAg (residues 540) having been shown to increase ssDNA binding activity (41) (Fig. 5A).…”

Section: Resultsmentioning

confidence: 99%

Large T Antigen Promotes JC Virus Replication in G2-arrested Cells by Inducing ATM- and ATR-mediated G2 Checkpoint Signaling

Orba

Suzuki

Makino

et al. 2010

Journal of Biological Chemistry

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The human polyomavirus JC virus (JCV) 2 is the causative agent of progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease of the central nervous system. JCV infection usually occurs during childhood, but remains subclinical. However, opportunistic reactivation of JCV results in the development of PML in individuals with a compromised immune system, such as those with acquired immunodeficiency syndrome (AIDS) or advanced-stage malignant tumors, or those recently having undergone organ transplantation with immunosuppressive therapy (1). There is currently no effective or specific therapy for PML, even though the incidence of this condition is increasing with the growing number of individuals with AIDS.JCV is a small virus with a double-stranded DNA genome that encodes early proteins (large T antigen, small t antigen, and TЈ antigen) and late proteins (VP1, VP2, VP3, and agnoprotein) (2). The entry of JCV into the nucleus of an infected cell is followed by transcription of the early genes and the production of large T antigen (TAg). The replication of JCV DNA progresses in association with the accumulation of TAg, which subsequently stimulates transcription of late genes and represses that of the early genes (3). JCV TAg shares 72% amino acid sequence identity with TAg of simian virus 40 (SV40), another primate polyomavirus, and, like SV40 TAg, it is necessary for replication of the viral genome as a result of its DNA binding and helicase activities. The replication of polyomaviruses also requires DNA replication proteins of the host cell, such as DNA polymerase ␣, topoisomerases, and replication protein A (RPA) (4, 5), with such host cell factors being thought to serve as determinants of host specificity (6).The utilization of such cellular proteins requires that polyomaviruses replicate in a phase of the cell cycle in which they are available. Polyomavirus TAg thus modulates cellular signaling pathways to induce quiescent cells to enter S phase, in which cellular DNA is replicated (7). A key event in this process is the interaction of TAg with members of the retinoblastoma protein family, which results in inactivation of retinoblastoma protein and in consequent progression of the cell cycle (8). Moreover, polyomaviruses are thought to take advantage of the DNA damage response to enhance viral replication. SV40 lytic infection thus triggers the DNA damage checkpoint, resulting in a bypass of mitosis and additional replication of cellular and viral DNA (9), and murine polyomavirus-infected cells accumulate in S and G 2 phases (10). Replication of viral DNA in cells *

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“…Our attention was initially drawn to SLX4 because it was identified as a target of the ATM/ATR protein kinases Mu et al, 2007). To gain insight into SLX4 function, we performed a proteomic analysis of SLX4 complexes purified from 293TREX cells harboring an inducible SLX4-HA lentivirus.…”

Section: Btbd12 (Slx4) Associates With Known Dna Repair Factorsmentioning

confidence: 99%

Mammalian BTBD12/SLX4 Assembles A Holliday Junction Resolvase and Is Required for DNA Repair

Svendsen¹,

Smogorzewska²,

Sowa³

et al. 2009

Journal of End-to-End-testing

199

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SummaryStructure-specific endonucleases mediate repair of DNA structures formed from replication fork collapse or during double-strand break (DSB) repair. Here we identify BTBD12 as the human ortholog of the budding yeast DNA repair factor Slx4p and D. melanogaster MUS312. Human SLX4 forms a multiprotein complex with the ERCC4(XPF)-ERCC1, MUS81-EME1, and SLX1 endonucleases, and also associates with MSH2/MSH3 mismatch repair complex, telomere binding complex TERF2(TRF2)-TERF2IP(RAP1), the protein kinase PLK1 and the uncharacterized protein C20orf94. Depletion of SLX4 causes sensitivity to mitomycin C and camptothecin, and reduces the efficiency of DSB repair in vivo. SLX4 complexes cleave 3'-flap, 5'-flap and replication fork structures; yet unlike other endonucleases associated with SLX4, the SLX1-SLX4 module promotes symmetrical cleavage of static and migrating Holliday junctions (HJs), identifying SLX1-SLX4 as a HJ resolvase. Thus, SLX4 assembles a modular tool-kit for repair of specific types of DNA lesions and is critical for cellular responses to replication fork failure.

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A Proteomic Analysis of Ataxia Telangiectasia-mutated (ATM)/ATM-Rad3-related (ATR) Substrates Identifies the Ubiquitin-Proteasome System as a Regulator for DNA Damage Checkpoints

Cited by 169 publications

References 32 publications

Cleavage of the BRCT tandem domains of nibrin by the 657del5 mutation affects the DNA damage response less than the Arg215Trp mutation

Cleavage of the BRCT tandem domains of nibrin by the 657del5 mutation affects the DNA damage response less than the Arg215Trp mutation

Large T Antigen Promotes JC Virus Replication in G2-arrested Cells by Inducing ATM- and ATR-mediated G2 Checkpoint Signaling

Mammalian BTBD12/SLX4 Assembles A Holliday Junction Resolvase and Is Required for DNA Repair

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