scholarly journals Aberrant monomethylation of histone H4 lysine 20 activates the DNA damage checkpoint in Drosophila melanogaster

2007 ◽  
Vol 176 (2) ◽  
pp. 155-162 ◽  
Author(s):  
Ayako Sakaguchi ◽  
Ruth Steward
Keyword(s):  
Dna Damage ◽  
Double Mutant ◽  
Chromosome Condensation ◽  
Cyclin B ◽  
Order Structure ◽  
Dna Damage Checkpoint ◽  
Histone H4 ◽  
Mitotic Progression ◽  
Strong Reduction ◽  
Early Mitosis

PR-Set7 is a histone methyltransferase that specifically monomethylates histone H4 lysine 20 (K20) and is essential for cell proliferation. Our results show that in PR-Set7 mutants, the DNA damage checkpoint is activated. This phenotype is manifested by reduction in both the mitotic and the S phase indexes, a delay in the progression through early mitosis, and strong reduction of cyclin B. Furthermore, in a double mutant of PR-Set7 and mei-41 (the fly ATR orthologue), the abnormalities of mitotic progression and the cyclin B protein level were rescued. PR-Set7 also showed a defect in chromosome condensation that was enhanced in the double mutant. We therefore propose that monomethylated H4K20 is involved in the maintenance of proper higher order structure of DNA and is consequently essential for chromosome condensation.

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.

scholarly journals Proteins in the Nutrient-Sensing and DNA Damage Checkpoint Pathways Cooperate to Restrain Mitotic Progression following DNA Damage

PLoS Genetics ◽  
2011 ◽  
Vol 7 (7) ◽  
pp. e1002176 ◽  
Author(s):  
Jennifer S. Searle ◽  
Matthew D. Wood ◽  
Mandeep Kaur ◽  
David V. Tobin ◽  
Yolanda Sanchez
Keyword(s):  
Dna Damage ◽  
Nutrient Sensing ◽  
Dna Damage Checkpoint ◽  
Mitotic Progression

scholarly journals The inhibition of checkpoint activation by telomeres does not involve exclusion of dimethylation of histone H4 lysine 20 (H4K20me2)

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 1027
Author(s):  
Julien Audry ◽  
Jinyu Wang ◽  
Jessica R. Eisenstatt ◽  
Kathleen L. Berkner ◽  
Kurt W. Runge
Keyword(s):  
Dna Damage ◽  
Protein Complexes ◽  
Dna Damage Checkpoint ◽  
Short Report ◽  
Dna Repeats ◽  
Histone H4 ◽  
Wild Type ◽  
Telomeric Dna ◽  
Checkpoint Signaling ◽  
Eukaryotic Chromosome

DNA double-strand (DSBs) breaks activate the DNA damage checkpoint machinery to pause or halt the cell cycle.  Telomeres, the specific DNA-protein complexes at linear eukaryotic chromosome ends, are capped DSBs that do not activate DNA damage checkpoints.  This “checkpoint privileged” status of telomeres was previously investigated in the yeast Schizosaccharomyces pombe lacking the major double-stranded telomere DNA binding protein Taz1.  Telomeric DNA repeats in cells lacking Taz1 are 10 times longer than normal and contain single-stranded DNA regions.  DNA damage checkpoint proteins associate with these damaged telomeres, but the DNA damage checkpoint is not activated.  This severing of the DNA damage checkpoint signaling pathway was reported to stem from exclusion of histone H4 lysine 20 dimethylation (H4K20me2) from telomeric nucleosomes in both wild type cells and cells lacking Taz1.  However, experiments to identify the mechanism of this exclusion failed, prompting our re-evaluation of H4K20me2 levels at telomeric chromatin.  In this short report, we used an extensive series of controls to identify an antibody specific for the H4K20me2 modification and show that the level of this modification is the same at telomeres and internal loci in both wild type cells and those lacking Taz1.  Consequently, telomeres must block activation of the DNA Damage Response by another mechanism that remains to be determined.

scholarly journals Yeast Rad52 and Rad51 Recombination Proteins Define a Second Pathway of DNA Damage Assessment in Response to a Single Double-Strand Break

2003 ◽  
Vol 23 (23) ◽  
pp. 8913-8923 ◽  
Author(s):  
Sang Eun Lee ◽  
Achille Pellicioli ◽  
Moreshwar B. Vaze ◽  
Neal Sugawara ◽  
Anna Malkova ◽  
...  
Keyword(s):  
Dna Damage ◽  
Damage Assessment ◽  
Double Mutant ◽  
Strand Break ◽  
Double Strand Break ◽  
Dna Damage Checkpoint ◽  
Checkpoint Protein ◽  
Ssdna Binding ◽  
Recombination Proteins ◽  
Truncation Mutant

ABSTRACT Saccharomyces cells with a single unrepaired double-strand break adapt after checkpoint-mediated G2/M arrest. We have found that both Rad51 and Rad52 recombination proteins play key roles in adaptation. Cells lacking Rad51p fail to adapt, but deleting RAD52 suppresses rad51Δ. rad52Δ also suppresses adaptation defects of srs2Δ mutants but not those of yku70Δ or tid1Δ mutants. Neither rad54Δ nor rad55Δ affects adaptation. A Rad51 mutant that fails to interact with Rad52p is adaptation defective; conversely, a C-terminal truncation mutant of Rad52p, impaired in interaction with Rad51p, is also adaptation defective. In contrast, rad51-K191A, a mutation that abolishes recombination and results in a protein that does not bind to single-stranded DNA (ssDNA), supports adaptation, as do Rad51 mutants impaired in interaction with Rad54p or Rad55p. An rfa1-t11 mutation in the ssDNA binding complex RPA partially restores adaptation in rad51Δ mutants and fully restores adaptation in yku70Δ and tid1Δ mutants. Surprisingly, although neither rfa1-t11 nor rad52Δ mutants are adaptation defective, the rad52Δ rfa1-t11 double mutant fails to adapt and exhibits the persistent hyperphosphorylation of the DNA damage checkpoint protein Rad53 after HO induction. We suggest that monitoring of the extent of DNA damage depends on independent binding of RPA and Rad52p to ssDNA, with Rad52p's activity modulated by Rad51p whereas RPA's action depends on Tid1p.

The DNA damage checkpoint and PKA pathways converge on APC substrates and Cdc20 to regulate mitotic progression

2004 ◽  
Vol 6 (2) ◽  
pp. 138-145 ◽  
Author(s):  
Jennifer S. Searle ◽  
Kaila L. Schollaert ◽  
Benjamin J. Wilkins ◽  
Yolanda Sanchez
Keyword(s):  
Dna Damage ◽  
Dna Damage Checkpoint ◽  
Mitotic Progression

Genetic and Physical Interactions BetweenDPB11andDDC1in the Yeast DNA Damage Response Pathway

Genetics ◽  
2002 ◽  
Vol 160 (4) ◽  
pp. 1295-1304 ◽  
Author(s):  
Hong Wang ◽  
Stephen J Elledge
Keyword(s):  
Dna Damage ◽  
Protein Interactions ◽  
Double Mutant ◽  
Dna Damage Checkpoint ◽  
Restrictive Temperature ◽  
Checkpoint Control ◽  
Protein Protein Interactions ◽  
Physical Interactions ◽  
And Function ◽  
Dna Damage Response Pathway

AbstractDPB11 is essential for DNA replication and S/M checkpoint control in Saccharomyces cerevisiae. The Dpb11 protein contains four BRCT domains, which have been proposed to be involved in protein-protein interactions. To further investigate the regulation and function of Dpb11, a yeast two-hybrid screen was carried out to identify proteins that physically interact with Dpb11. One positive clone isolated from the screen encoded a carboxyl-terminal fragment of Ddc1 (339–612 aa). Ddc1 is a DNA damage checkpoint protein, which, together with Mec3 and Rad17, has been proposed to form a PCNA-like complex and acts upstream in the DNA damage checkpoint pathways. We further determined that the carboxyl region of Dpb11 is required for its interaction with Ddc1. DDC1 and DPB11 also interact genetically. The Δddc1 dpb11-1 double mutant is more UV and MMS sensitive than the Δddc1 or the dpb11-1 single mutants. Furthermore, the double mutant is more hydroxyurea sensitive and displayed a lower restrictive temperature than dpb11-1. These results suggest that DPB11 and DDC1 may function in the same or parallel pathways after DNA damage and that DDC1 may play a role in responding to replication defects.

scholarly journals The inhibition of checkpoint activation by telomeres does not involve exclusion of dimethylation of histone H4 lysine 20 (H4K20me2)

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 1027 ◽  
Author(s):  
Julien Audry ◽  
Jinyu Wang ◽  
Jessica R. Eisenstatt ◽  
Kathleen L. Berkner ◽  
Kurt W. Runge
Keyword(s):  
Dna Damage ◽  
Protein Complexes ◽  
Dna Damage Checkpoint ◽  
Short Report ◽  
Dna Repeats ◽  
Histone H4 ◽  
Wild Type ◽  
Dna Double Strand Breaks ◽  
Checkpoint Signaling ◽  
Eukaryotic Chromosome

DNA double-strand breaks (DSBs) activate the DNA damage checkpoint machinery to pause or halt the cell cycle.  Telomeres, the specific DNA-protein complexes at linear eukaryotic chromosome ends, are capped DSBs that do not activate DNA damage checkpoints.  This “checkpoint privileged” status of telomeres was previously investigated in the yeast Schizosaccharomyces pombelacking the major double-stranded telomere DNA binding protein Taz1. Telomeric DNA repeats in cells lacking Taz1 are 10 times longer than normal and contain single-stranded DNA regions. DNA damage checkpoint proteins associate with these damaged telomeres, but the DNA damage checkpoint is not activated. This severing of the DNA damage checkpoint signaling pathway was reported to stem from exclusion of histone H4 lysine 20 dimethylation (H4K20me2) from telomeric nucleosomes in both wild type cells and cells lacking Taz1.  However, experiments to identify the mechanism of this exclusion failed, prompting our re-evaluation of H4K20me2 levels at telomeric chromatin.  In this short report, we used an extensive series of controls to identify an antibody specific for the H4K20me2 modification and show that the level of this modification is the same at telomeres and internal loci in both wild type cells and those lacking Taz1.  Consequently, telomeres must block activation of the DNA Damage Response by another mechanism that remains to be determined.

scholarly journals The Tumor Suppressor MIG6 Controls Mitotic Progression and the G2/M DNA Damage Checkpoint by Stabilizing the WEE1 Kinase

Cell Reports ◽  
2018 ◽  
Vol 24 (5) ◽  
pp. 1278-1289 ◽  
Author(s):  
Mari Sasaki ◽  
Takeshi Terabayashi ◽  
Stefanie M. Weiss ◽  
Ingvar Ferby
Keyword(s):  
Dna Damage ◽  
Tumor Suppressor ◽  
Dna Damage Checkpoint ◽  
Mitotic Progression ◽  
Wee1 Kinase

scholarly journals Mediator of DNA Damage Checkpoint 1 (MDC1) Regulates Mitotic Progression

2009 ◽  
Vol 284 (49) ◽  
pp. 33939-33948 ◽  
Author(s):  
Kelly Townsend ◽  
Helen Mason ◽  
Andrew N. Blackford ◽  
Edward S. Miller ◽  
J. Ross Chapman ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Checkpoint ◽  
Mitotic Progression
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