scholarly journals Differential genetic interactions between Sgs1, DNA-damage checkpoint components and DNA repair factors in the maintenance of chromosome stability

2011 ◽  
Vol 2 (1) ◽  
pp. 8 ◽  
Author(s):  
Lillian Doerfler ◽  
Lorena Harris ◽  
Emilie Viebranz ◽  
Kristina H Schmidt
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Genetic Interactions ◽  
Dna Damage Checkpoint ◽  
Chromosome Stability

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 Co-inhibition of HDAC and MLL-menin interaction targets MLL-rearranged acute myeloid leukemia cells via disruption of DNA damage checkpoint and DNA repair

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Jing Ye ◽  
Jie Zha ◽  
Yuanfei Shi ◽  
Yin Li ◽  
Delin Yuan ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Clinical Investigation ◽  
Combined Treatment ◽  
Single Agent ◽  
Ros Generation ◽  
Dna Damage Checkpoint ◽  
Acute Myeloid

Abstract While the aberrant translocation of the mixed-lineage leukemia (MLL) gene drives pathogenesis of acute myeloid leukemia (AML), it represents an independent predictor for poor prognosis of adult AML patients. Thus, small molecule inhibitors targeting menin-MLL fusion protein interaction have been emerging for the treatment of MLL-rearranged AML. As both inhibitors of histone deacetylase (HDAC) and menin-MLL interaction target the transcription-regulatory machinery involving epigenetic regulation of chromatin remodeling that governs the expression of genes involved in tumorigenesis, we hypothesized that these two classes of agents might interact to kill MLL-rearranged (MLL-r) AML cells. Here, we report that the combination treatment with subtoxic doses of the HDAC inhibitor chidamide and the menin-MLL interaction inhibitor MI-3 displayed a highly synergistic anti-tumor activity against human MLL-r AML cells in vitro and in vivo, but not those without this genetic aberration. Mechanistically, co-exposure to chidamide and MI-3 led to robust apoptosis in MLL-r AML cells, in association with loss of mitochondrial membrane potential and a sharp increase in ROS generation. Combined treatment also disrupted DNA damage checkpoint at the level of CHK1 and CHK2 kinases, rather than their upstream kinases (ATR and ATM), as well as DNA repair likely via homologous recombination (HR), but not non-homologous end joining (NHEJ). Genome-wide RNAseq revealed gene expression alterations involving several potential signaling pathways (e.g., cell cycle, DNA repair, MAPK, NF-κB) that might account for or contribute to the mechanisms of action underlying anti-leukemia activity of chidamide and MI-3 as a single agent and particularly in combination in MLL-r AML. Collectively, these findings provide a preclinical basis for further clinical investigation of this novel targeted strategy combining HDAC and Menin-MLL interaction inhibitors to improve therapeutic outcomes in a subset of patients with poor-prognostic MLL-r leukemia.

scholarly journals HIV-1 Vpr counteracts HLTF-mediated restriction of HIV-1 infection in T cells

2019 ◽  
Vol 116 (19) ◽  
pp. 9568-9577 ◽  
Author(s):  
Junpeng Yan ◽  
Ming-Chieh Shun ◽  
Yi Zhang ◽  
Caili Hao ◽  
Jacek Skowronski
Keyword(s):  
Dna Damage ◽  
T Cells ◽  
Dna Repair ◽  
Dna Helicase ◽  
Cycle Phase ◽  
Nuclear Pore ◽  
Dna Damage Checkpoint ◽  
Nuclear Pore Complexes ◽  
Chromosomal Dna ◽  
Hiv 1

Lentiviruses, including HIV-1, possess the ability to enter the nucleus through nuclear pore complexes and can infect interphase cells, including those actively replicating chromosomal DNA. Viral accessory proteins hijack host cell E3 enzymes to antagonize intrinsic defenses, and thereby provide a more permissive environment for virus replication. The HIV-1 Vpr accessory protein reprograms CRL4DCAF1 E3 to antagonize select postreplication DNA repair enzymes and activates the DNA damage checkpoint in the G2 cell cycle phase. However, little is known about the roles played by these Vpr targets in HIV-1 replication. Here, using a sensitive pairwise replication competition assay, we show that Vpr endows HIV-1 with a strong replication advantage in activated primary CD4+ T cells and established T cell lines. This effect is disabled by a Vpr mutation that abolishes binding to CRL4DCAF1 E3, thereby disrupting Vpr antagonism of helicase-like transcription factor (HLTF) DNA helicase and other DNA repair pathway targets, and by another mutation that prevents induction of the G2 DNA damage checkpoint. Consistent with these findings, we also show that HLTF restricts HIV-1 replication, and that this restriction is antagonized by HIV-1 Vpr. Furthermore, our data imply that HIV-1 Vpr uses additional, yet to be identified mechanisms to facilitate HIV-1 replication in T cells. Overall, we demonstrate that multiple aspects of the cellular DNA repair machinery restrict HIV-1 replication in dividing T cells, the primary target of HIV-1 infection, and describe newly developed approaches to dissect key components.

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 Disease-associated DNA2 nuclease–helicase protects cells from lethal chromosome under-replication

2020 ◽  
Author(s):  
Benoît Falquet ◽  
Gizem Ölmezer ◽  
Franz Enkner ◽  
Dominique Klein ◽  
Kiran Challa ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Dna Damage ◽  
Cell Death ◽  
Dna Repair ◽  
Dna Damage Checkpoint ◽  
Replication Forks ◽  
Checkpoint Activation ◽  
Essential Function ◽  
Mutant Cells ◽  
Lagging Strand

Abstract DNA2 is an essential nuclease–helicase implicated in DNA repair, lagging-strand DNA synthesis, and the recovery of stalled DNA replication forks (RFs). In Saccharomyces cerevisiae, dna2Δ inviability is reversed by deletion of the conserved helicase PIF1 and/or DNA damage checkpoint-mediator RAD9. It has been suggested that Pif1 drives the formation of long 5′-flaps during Okazaki fragment maturation, and that the essential function of Dna2 is to remove these intermediates. In the absence of Dna2, 5′-flaps are thought to accumulate on the lagging strand, resulting in DNA damage-checkpoint arrest and cell death. In line with Dna2’s role in RF recovery, we find that the loss of Dna2 results in severe chromosome under-replication downstream of endogenous and exogenous RF-stalling. Importantly, unfaithful chromosome replication in Dna2-mutant cells is exacerbated by Pif1, which triggers the DNA damage checkpoint along a pathway involving Pif1’s ability to promote homologous recombination-coupled replication. We propose that Dna2 fulfils its essential function by promoting RF recovery, facilitating replication completion while suppressing excessive RF restart by recombination-dependent replication (RDR) and checkpoint activation. The critical nature of Dna2’s role in controlling the fate of stalled RFs provides a framework to rationalize the involvement of DNA2 in Seckel syndrome and cancer.

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