Eukaryotic DNA damage checkpoint activation in response to double-strand breaks

2011 ◽  
Vol 69 (9) ◽  
pp. 1447-1473 ◽  
Author(s):  
Karen Finn ◽  
Noel Francis Lowndes ◽  
Muriel Grenon
Keyword(s):  
Dna Damage ◽  
Double Strand Breaks ◽  
Dna Damage Checkpoint ◽  
Checkpoint Activation ◽  
Strand Breaks ◽  
Eukaryotic Dna

scholarly journals Vertebrate cells genetically deficient for Cdc14A or Cdc14B retain DNA damage checkpoint proficiency but are impaired in DNA repair

2010 ◽  
Vol 189 (4) ◽  
pp. 631-639 ◽  
Author(s):  
Annamaria Mocciaro ◽  
Eli Berdougo ◽  
Kang Zeng ◽  
Elizabeth Black ◽  
Paola Vagnarelli ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Retinal Pigment ◽  
Double Strand Breaks ◽  
Retinal Pigment Epithelial Cells ◽  
Dna Damage Checkpoint ◽  
Dna Double Strand Breaks ◽  
Central Function ◽  
Strand Breaks ◽  
Human Telomerase

A recent study suggested that human Cdc14B phosphatase has a central function in the G2 DNA damage checkpoint. In this study, we show that chicken DT40, human HCT116, and human telomerase reverse transcription–immortalized retinal pigment epithelial cells deleted for the Cdc14A or Cdc14B gene are DNA damage checkpoint proficient and arrest efficiently in G2 in response to irradiation. Cdc14A knockout (KO) or Cdc14B-KO cells also maintain normal levels of Chk1 and Chk2 activation after irradiation. Surprisingly, however, irradiation-induced γ-H2A.X foci and DNA double-strand breaks persist longer in Cdc14A-KO or Cdc14B-KO cells than controls, suggesting that Cdc14 phosphatases are required for efficient DNA repair.

scholarly journals Schizosaccharomyces pombeDss1p Is a DNA Damage Checkpoint Protein That Recruits Rad24p, Cdc25p, and Rae1p to DNA Double-strand Breaks

2010 ◽  
Vol 285 (19) ◽  
pp. 14122-14133 ◽  
Author(s):  
Saravana P. Selvanathan ◽  
Anjan G. Thakurta ◽  
Jothy Dhakshnamoorthy ◽  
Ming Zhou ◽  
Timothy D. Veenstra ◽  
...  
Keyword(s):  
Dna Damage ◽  
Double Strand Breaks ◽  
Dna Damage Checkpoint ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Checkpoint Protein

scholarly journals DNA damage triggers increased mobility of chromosomes in G1-phase cells

2019 ◽  
Vol 30 (21) ◽  
pp. 2620-2625 ◽  
Author(s):  
Michael J. Smith ◽  
Eric E. Bryant ◽  
Fraulin J. Joseph ◽  
Rodney Rothstein
Keyword(s):  
Dna Damage ◽  
S Phase ◽  
Double Strand Breaks ◽  
Homology Search ◽  
G1 Phase ◽  
Dna Damage Checkpoint ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Global Mobility ◽  
Break Site

During S phase in Saccharomyces cerevisiae, chromosomal loci become mobile in response to DNA double-strand breaks both at the break site (local mobility) and throughout the nucleus (global mobility). Increased nuclear exploration is regulated by the recombination machinery and the DNA damage checkpoint and is likely an important aspect of homology search. While mobility in response to DNA damage has been studied extensively in S phase, the response in interphase has not, and the question of whether homologous recombination proceeds to completion in G1 phase remains controversial. Here, we find that global mobility is triggered in G1 phase. As in S phase, global mobility in G1 phase is controlled by the DNA damage checkpoint and the Rad51 recombinase. Interestingly, despite the restriction of Rad52 mediator foci to S phase, Rad51 foci form at high levels in G1 phase. Together, these observations indicate that the recombination and checkpoint machineries promote global mobility in G1 phase, supporting the notion that recombination can occur in interphase diploids.

scholarly journals LC8/DYNLL1 is a 53BP1 effector and regulates checkpoint activation

2019 ◽  
Vol 47 (12) ◽  
pp. 6236-6249 ◽  
Author(s):  
Kirk L West ◽  
Jessica L Kelliher ◽  
Zhanzhan Xu ◽  
Liwei An ◽  
Megan R Reed ◽  
...  
Keyword(s):  
Dna Damage ◽  
Double Strand Breaks ◽  
Parp Inhibition ◽  
Current Evidence ◽  
Dependent Manner ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Checkpoint Activation ◽  
Strand Breaks ◽  
Non Homologous End Joining

Abstract The tumor suppressor protein 53BP1 plays key roles in response to DNA double-strand breaks (DSBs) by serving as a master scaffold at the damaged chromatin. Current evidence indicates that 53BP1 assembles a cohort of DNA damage response (DDR) factors to distinctly execute its repertoire of DSB responses, including checkpoint activation and non-homologous end joining (NHEJ) repair. Here, we have uncovered LC8 (a.k.a. DYNLL1) as an important 53BP1 effector. We found that LC8 accumulates at laser-induced DNA damage tracks in a 53BP1-dependent manner and requires the canonical H2AX-MDC1-RNF8-RNF168 signal transduction cascade. Accordingly, genetic inactivation of LC8 or its interaction with 53BP1 resulted in checkpoint defects. Importantly, loss of LC8 alleviated the hypersensitivity of BRCA1-depleted cells to ionizing radiation and PARP inhibition, highlighting the 53BP1-LC8 module in counteracting BRCA1-dependent functions in the DDR. Together, these data establish LC8 as an important mediator of a subset of 53BP1-dependent DSB responses.

scholarly journals Checkpoint Responses to DNA Double-Strand Breaks

2020 ◽  
Vol 89 (1) ◽  
pp. 103-133 ◽  
Author(s):  
David P. Waterman ◽  
James E. Haber ◽  
Marcus B. Smolka
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Dna Damage ◽  
Model System ◽  
Double Strand Breaks ◽  
Dna Damage Checkpoint ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Dna Dsbs ◽  
Cell Lethality

Cells confront DNA damage in every cell cycle. Among the most deleterious types of DNA damage are DNA double-strand breaks (DSBs), which can cause cell lethality if unrepaired or cancers if improperly repaired. In response to DNA DSBs, cells activate a complex DNA damage checkpoint (DDC) response that arrests the cell cycle, reprograms gene expression, and mobilizes DNA repair factors to prevent the inheritance of unrepaired and broken chromosomes. Here we examine the DDC, induced by DNA DSBs, in the budding yeast model system and in mammals.

scholarly journals Association of Rad9 with Double-Strand Breaks through a Mec1-Dependent Mechanism

2004 ◽  
Vol 24 (8) ◽  
pp. 3277-3285 ◽  
Author(s):  
Takahiro Naiki ◽  
Tatsushi Wakayama ◽  
Daisuke Nakada ◽  
Kunihiro Matsumoto ◽  
Katsunori Sugimoto
Keyword(s):  
Dna Damage ◽  
Double Strand Breaks ◽  
Dna Damage Checkpoint ◽  
Dependent Manner ◽  
Wild Type ◽  
Strand Breaks ◽  
Dependent Mechanism ◽  
In Cells

ABSTRACT Rad9 is required for the activation of DNA damage checkpoint pathways in budding yeast. Rad9 is phosphorylated after DNA damage in a Mec1- and Tel1-dependent manner and subsequently interacts with Rad53. This Rad9-Rad53 interaction has been suggested to trigger the activation and phosphorylation of Rad53. Here we show that Mec1 controls the Rad9 accumulation at double-strand breaks (DSBs). Rad9 was phosphorylated after DSB induction and associated with DSBs. However, its phosphorylation and association with DSBs were significantly decreased in cells carrying a mec1Δ or kinase-negative mec1 mutation. Mec1 phosphorylated the S/TQ motifs of Rad9 in vitro, the same motifs that are phosphorylated after DNA damage in vivo. In addition, multiple mutations in the Rad9 S/TQ motifs resulted in its defective association with DSBs. Phosphorylation of Rad9 was partially defective in cells carrying a weak mec1 allele (mec1-81), whereas its association with DSBs occurred efficiently in the mec1-81 mutants, as found in wild-type cells. However, the Rad9-Rad53 interaction after DSB induction was significantly decreased in mec1-81 mutants, as it was in mec1Δ mutants. Deletion mutation in RAD53 did not affect the association of Rad9 with DSBs. Our results suggest that Mec1 promotes association of Rad9 with sites of DNA damage, thereby leading to full phosphorylation of Rad9 and its interaction with Rad53.

scholarly journals TIF1 Activates the Intra-S-Phase Checkpoint Response in the Diploid Micronucleus and Amitotic Polyploid Macronucleus of Tetrahymena

2006 ◽  
Vol 17 (12) ◽  
pp. 5185-5197 ◽  
Author(s):  
J. Sebastian Yakisich ◽  
Pamela Y. Sandoval ◽  
Tara L. Morrison ◽  
Geoffrey M. Kapler
Keyword(s):  
Dna Damage ◽  
Genotoxic Stress ◽  
S Phase ◽  
Double Strand Breaks ◽  
Wild Type ◽  
Checkpoint Activation ◽  
Checkpoint Response ◽  
Strand Breaks ◽  
Origin Binding Protein ◽  
S Phase Checkpoint

The ribosomal DNA origin binding protein Tif1p regulates the timing of rDNA replication and is required globally for proper S-phase progression and division of the Tetrahymena thermophila macronucleus. Here, we show that Tif1p safeguards chromosomes from DNA damage in the mitotic micronucleus and amitotic macronucleus. TIF1p localization is dynamically regulated as it moves into the micro- and macronucleus during the respective S phases. TIF1 disruption mutants are hypersensitive to hydroxyurea and methylmethanesulfonate, inducers of DNA damage and intra-S-phase checkpoint arrest in all examined eukaryotes. TIF1 mutants incur double-strand breaks in the absence of exogenous genotoxic stress, destabilizing all five micronuclear chromosomes. Wild-type Tetrahymena elicits an intra-S-phase checkpoint response that is induced by hydroxyurea and suppressed by caffeine, an inhibitor of the apical checkpoint kinase ATR/MEC1. In contrast, hydroxyurea-challenged TIF1 mutants fail to arrest in S phase or exhibit caffeine-sensitive Rad51 overexpression, indicating the involvement of TIF1 in checkpoint activation. Although aberrant micro- and macronuclear division occurs in TIF1 mutants and caffeine-treated wild-type cells, TIF1p bears no similarity to ATR or its substrates. We propose that TIF1 and ATR function in the same epistatic pathway to regulate checkpoint responses in the diploid mitotic micronucleus and polyploid amitotic macronucleus.

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