scholarly journals TopBP1 and ATR Colocalization at Meiotic Chromosomes: Role of TopBP1/Cut5 in the Meiotic Recombination Checkpoint

2004 ◽  
Vol 15 (4) ◽  
pp. 1568-1579 ◽  
Author(s):  
David Perera ◽  
Livia Perez-Hidalgo ◽  
Peter B. Moens ◽  
Kaarina Reini ◽  
Nicholas Lakin ◽  
...  
Keyword(s):  
Dna Damage ◽  
Meiotic Recombination ◽  
Early Prophase ◽  
Dna Damage Checkpoint ◽  
Dna Double Strand Breaks ◽  
Direct Role ◽  
Meiotic Chromosomes ◽  
Defective Mutant ◽  
Recombination Checkpoint

Mammalian TopBP1 is a BRCT domain–containing protein whose function in mitotic cells is linked to replication and DNA damage checkpoint. Here, we study its possible role during meiosis in mice. TopBP1 foci are abundant during early prophase I and localize mainly to histone γ-H2AX–positive domains, where DNA double–strand breaks (required to initiate recombination) occur. Strikingly, TopBP1 showed a pattern almost identical to that of ATR, a PI3K-like kinase involved in mitotic DNA damage checkpoint. In the synapsis-defective Fkbp6-/- mouse, TopBP1 heavily stains unsynapsed regions of chromosomes. We also tested whether Schizosaccharomyces pombe Cut5 (the TopBP1 homologue) plays a role in the meiotic recombination checkpoint, like spRad3, the ATR homologue. Indeed, we found that a cut5 mutation suppresses the checkpoint-dependent meiotic delay of a meiotic recombination defective mutant, indicating a direct role of the Cut5 protein in the meiotic checkpoint. Our findings suggest that ATR and TopBP1 monitor meiotic recombination and are required for activation of the meiotic recombination checkpoint.

scholarly journals Arabidopsis Mediator subunit 17 connects transcription with DNA repair after UV-B exposure

2021 ◽  
Author(s):  
Marisol Giustozzi ◽  
Santiago Freytes ◽  
Aime Jaskolowski ◽  
Micaela Lichy ◽  
Julieta L. Mateos ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Transcription Initiation ◽  
Plant Responses ◽  
Repair System ◽  
Root Tips ◽  
Direct Role ◽  
Altered Expression ◽  
Eukaryotic Organisms

Mediator 17 (MED17) is a subunit of the Mediator complex that regulates transcription initiation in eukaryotic organisms. In yeast and humans, MED17 also participates in DNA repair, physically interacting with proteins of the Nucleotide Excision DNA Repair system. We here analyzed the role of MED17 in Arabidopsis plants exposed to UV-B radiation, which role has not been previously described. Comparison of med17 mutant transcriptome to that of WT plants showed that almost one third of transcripts with altered expression in med17 plants are also changed by UV-B exposure in WT plants. To validate the role of MED17 in UV-B irradiated plants, plant responses to UV-B were analyzed, including flowering time, DNA damage accumulation and programmed cell death in the meristematic cells of the root tips. Our results show that med17 and OE MED17 plants have altered responses to UV-B; and that MED17 participates in various aspects of the DNA damage response (DDR). Increased sensitivity to DDR after UV-B in med17 plants can be due to altered regulation of UV-B responsive transcripts; but additionally MED17 physically interacts with DNA repair proteins, suggesting a direct role of this Mediator subunit during repair. Finally, we here also show that MED17 is necessary to regulate the DDR activated by ATR, and that PDCD5 overexpression reverts the deficiencies in DDR shown in med17 mutants. Together, the data presented demonstrates that MED17 is an important regulator of the DDR after UV-B radiation in Arabidopsis plants.

scholarly journals LATS1/WARTS phosphorylates MYPT1 to counteract PLK1 and regulate mammalian mitotic progression

2012 ◽  
Vol 197 (5) ◽  
pp. 625-641 ◽  
Author(s):  
Tatsuyuki Chiyoda ◽  
Naoyuki Sugiyama ◽  
Takatsune Shimizu ◽  
Hideaki Naoe ◽  
Yusuke Kobayashi ◽  
...  
Keyword(s):  
Dna Damage ◽  
Deoxyribonucleic Acid ◽  
Mitotic Exit ◽  
Dna Damage Checkpoint ◽  
Mitotic Progression ◽  
Myosin Phosphatase ◽  
G2 Checkpoint ◽  
Mitotic Exit Network ◽  
Kinase Screening

In the mitotic exit network of budding yeast, Dbf2 kinase phosphorylates and regulates Cdc14 phosphatase. In contrast, no phosphatase substrates of LATS1/WARTS kinase, the mammalian equivalent of Dbf2, has been reported. To address this discrepancy, we performed phosphoproteomic screening using LATS1 kinase. Screening identified MYPT1 (myosin phosphatase–targeting subunit 1) as a new substrate for LATS1. LATS1 directly and preferentially phosphorylated serine 445 (S445) of MYPT1. An MYPT1 mutant (S445A) failed to dephosphorylate Thr 210 of PLK1 (pololike kinase 1), thereby activating PLK1. This suggests that LATS1 promotes MYPT1 to antagonize PLK1 activity. Consistent with this, LATS1-depleted HeLa cells or fibroblasts from LATS1 knockout mice showed increased PLK1 activity. We also found deoxyribonucleic acid (DNA) damage–induced LATS1 activation caused PLK1 suppression via the phosphorylation of MYPT1 S445. Furthermore, LATS1 knockdown cells showed reduced G2 checkpoint arrest after DNA damage. These results indicate that LATS1 phosphorylates a phosphatase as does the yeast Dbf2 and demonstrate a novel role of LATS1 in controlling PLK1 at the G2 DNA damage checkpoint.

53BP1: function and mechanisms of focal recruitment

2009 ◽  
Vol 37 (4) ◽  
pp. 897-904 ◽  
Author(s):  
Jennifer E. FitzGerald ◽  
Muriel Grenon ◽  
Noel F. Lowndes
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Dna Damage Response ◽  
Dna Damage Checkpoint ◽  
Checkpoint Activation ◽  
Damage Response ◽  
Nuclear Structures ◽  
Genotoxic Insult ◽  
Covalent Histone Modifications

53BP1 (p53-binding protein 1) is classified as a mediator/adaptor of the DNA-damage response, and is recruited to nuclear structures termed foci following genotoxic insult. In the present paper, we review the functions of 53BP1 in DNA-damage checkpoint activation and DNA repair, and the mechanisms of its recruitment and activation following DNA damage. We focus in particular on the role of covalent histone modifications in this process.

scholarly journals Regulation of E2F1 by BRCT Domain-Containing Protein TopBP1

2003 ◽  
Vol 23 (9) ◽  
pp. 3287-3304 ◽  
Author(s):  
Kang Liu ◽  
Fang-Tsyr Lin ◽  
J. Michael Ruppert ◽  
Weei-Chin Lin
Keyword(s):  
Dna Damage ◽  
Cell Cycle Progression ◽  
Specific Interaction ◽  
Dna Damage Checkpoint ◽  
Brct Domain ◽  
Replication Forks ◽  
Direct Role ◽  
Dna Topoisomerase ◽  
E2f Transcription Factor ◽  
Stalled Replication Forks

ABSTRACT The E2F transcription factor integrates cellular signals and coordinates cell cycle progression. Our prior studies demonstrated selective induction and stabilization of E2F1 through ATM-dependent phosphorylation in response to DNA damage. Here we report that DNA topoisomerase IIβ binding protein 1 (TopBP1) regulates E2F1 during DNA damage. TopBP1 contains eight BRCT (BRCA1 carboxyl-terminal) motifs and upon DNA damage is recruited to stalled replication forks, where it participates in a DNA damage checkpoint. Here we demonstrated an interaction between TopBP1 and E2F1. The interaction depended on the amino terminus of E2F1 and the sixth BRCT domain of TopBP1. It was specific to E2F1 and was not observed in E2F2, E2F3, or E2F4. This interaction was induced by DNA damage and phosphorylation of E2F1 by ATM. Through this interaction, TopBP1 repressed multiple activities of E2F1, including transcriptional activity, induction of S-phase entry, and apoptosis. Furthermore, TopBP1 relocalized E2F1 from diffuse nuclear distribution to discrete punctate nuclear foci, where E2F1 colocalized with TopBP1 and BRCA1. Thus, the specific interaction between TopBP1 and E2F1 during DNA damage inhibits the known E2F1 activities but recruits E2F1 to a BRCA1-containing repair complex, suggesting a direct role of E2F1 in DNA damage checkpoint/repair at stalled replication forks.

scholarly journals Direct and Indirect Control of the Initiation of Meiotic Recombination by DNA Damage Checkpoint Mechanisms in Budding Yeast

PLoS ONE ◽  
2013 ◽  
Vol 8 (6) ◽  
pp. e65875 ◽  
Author(s):  
Bilge Argunhan ◽  
Sarah Farmer ◽  
Wing-Kit Leung ◽  
Yaroslav Terentyev ◽  
Neil Humphryes ◽  
...  
Keyword(s):  
Dna Damage ◽  
Meiotic Recombination ◽  
Budding Yeast ◽  
Dna Damage Checkpoint ◽  
Indirect Control

scholarly journals Inactivation of Ku-Mediated End Joining Suppresses mec1Δ Lethality by Depleting the Ribonucleotide Reductase Inhibitor Sml1 through a Pathway Controlled by Tel1 Kinase and the Mre11 Complex

2005 ◽  
Vol 25 (23) ◽  
pp. 10652-10664 ◽  
Author(s):  
Yves Corda ◽  
Sang Eun Lee ◽  
Sylvine Guillot ◽  
André Walther ◽  
Julie Sollier ◽  
...  
Keyword(s):  
Dna Damage ◽  
Ribonucleotide Reductase ◽  
Reductase Inhibitor ◽  
Nonhomologous End Joining ◽  
Dna Damage Checkpoint ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Strand Breaks ◽  
Ribonucleotide Reductase Inhibitor ◽  
Kinase Cascade

ABSTRACT RAD53 and MEC1 are essential Saccharomyces cerevisiae genes required for the DNA replication and DNA damage checkpoint responses. Their lethality can be suppressed by increasing the intracellular pool of deoxynucleotide triphosphates. We report that deletion of YKU70 or YKU80 suppresses mec1Δ, but not rad53Δ, lethality. We show that suppression of mec1Δ lethality is not due to Ku−-associated telomeric defects but rather results from the inability of Ku− cells to efficiently repair DNA double strand breaks by nonhomologous end joining. Consistent with these results, mec1Δ lethality is also suppressed by lif1Δ, which like yku70Δ and yku80Δ, prevents nonhomologous end joining. The viability of yku70Δ mec1Δ and yku80Δ mec1Δ cells depends on the ATM-related Tel1 kinase, the Mre11-Rad50-Xrs2 complex, and the DNA damage checkpoint protein Rad9. We further report that this Mec1-independent pathway converges with the Rad53/Dun1-regulated checkpoint kinase cascade and leads to the degradation of the ribonucleotide reductase inhibitor Sml1.

scholarly journals A Divergent Role of the SIRT1-TopBP1 Axis in Regulating Metabolic Checkpoint and DNA Damage Checkpoint

2014 ◽  
Vol 56 (5) ◽  
pp. 681-695 ◽  
Author(s):  
Tongzheng Liu ◽  
Yi-Hui Lin ◽  
Wenchuan Leng ◽  
Sung Yun Jung ◽  
Haoxing Zhang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Checkpoint

scholarly journals Regulation of Rtt107 Recruitment to Stalled DNA Replication Forks by the Cullin Rtt101 and the Rtt109 Acetyltransferase

2008 ◽  
Vol 19 (1) ◽  
pp. 171-180 ◽  
Author(s):  
Tania M. Roberts ◽  
Iram Waris Zaidi ◽  
Jessica A. Vaisica ◽  
Matthias Peter ◽  
Grant W. Brown
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Replication Forks ◽  
Chromatin Binding ◽  
Direct Role ◽  
Repair Enzymes ◽  
Damage Response ◽  
Stalled Replication Forks

RTT107 (ESC4, YHR154W) encodes a BRCA1 C-terminal domain protein that is important for recovery from DNA damage during S phase. Rtt107 is a substrate of the checkpoint kinase Mec1, and it forms complexes with DNA repair enzymes, including the nuclease subunit Slx4, but the role of Rtt107 in the DNA damage response remains unclear. We find that Rtt107 interacts with chromatin when cells are treated with compounds that cause replication forks to arrest. This damage-dependent chromatin binding requires the acetyltransferase Rtt109, but it does not require acetylation of the known Rtt109 target, histone H3-K56. Chromatin binding of Rtt107 also requires the cullin Rtt101, which seems to play a direct role in Rtt107 recruitment, because the two proteins are found in complex with each other. Finally, we provide evidence that Rtt107 is bound at or near stalled replication forks in vivo. Together, these results indicate that Rtt109, Rtt101, and Rtt107, which genetic evidence suggests are functionally related, form a DNA damage response pathway that recruits Rtt107 complexes to damaged or stalled replication forks.

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