scholarly journals Targeting Protein-Protein Interactions in the DNA Damage Response Pathways for Cancer Chemotherapy

2021 ◽  
Author(s):  
Kerry Silva McPherson ◽  
Dmitry Korzhnev
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Protein Interactions ◽  
Cell Cycle Progression ◽  
Protein Protein Interactions ◽  
Cycle Progression ◽  
Damage Recognition ◽  
Damage Response ◽  
Cellular Dna ◽  
Dna Damage Recognition

Cellular DNA damage response (DDR) is an extensive signaling network that orchestrates DNA damage recognition, repair and avoidance, cell cycle progression and cell death. DDR alternation is a hallmark of...

scholarly journals SETD2 alterations impair DNA damage recognition and lead to resistance to chemotherapy in leukemia

Blood ◽  
2017 ◽  
Vol 130 (24) ◽  
pp. 2631-2641 ◽  
Author(s):  
Brenton G. Mar ◽  
S. Haihua Chu ◽  
Josephine D. Kahn ◽  
Andrei V. Krivtsov ◽  
Richard Koche ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Mutation Rate ◽  
Histone 3 ◽  
Damage Recognition ◽  
Key Points ◽  
Damage Response ◽  
Dna Damage Recognition ◽  
Resistance To Chemotherapy

Key Points Alterations of SETD2, a histone 3 lysine 36 trimethyl (H3K36me3) transferase leads to resistance to DNA damaging-chemotherapy in leukemia. Low H3K36me3 levels impair DNA damage response and increase mutation rate, which may be targeted by H3K36me3 demethylase inhibition.

scholarly journals Overall Cdk activity modulates the DNA damage response in mammalian cells

2009 ◽  
Vol 187 (6) ◽  
pp. 773-780 ◽  
Author(s):  
Antonio Cerqueira ◽  
David Santamaría ◽  
Bárbara Martínez-Pastor ◽  
Miriam Cuadrado ◽  
Oscar Fernández-Capetillo ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Mammalian Cells ◽  
Cell Cycle Progression ◽  
Cyclin Dependent Kinase ◽  
Genome Maintenance ◽  
Cycle Progression ◽  
Damage Response ◽  
Dna Break ◽  
Specific Contribution

In response to DNA damage, cells activate a phosphorylation-based signaling cascade known as the DNA damage response (DDR). One of the main outcomes of DDR activation is inhibition of cyclin-dependent kinase (Cdk) activity to restrain cell cycle progression until lesions are healed. Recent studies have revealed a reverse connection by which Cdk activity modulates processing of DNA break ends and DDR activation. However, the specific contribution of individual Cdks to this process remains poorly understood. To address this issue, we have examined the DDR in murine cells carrying a defined set of Cdks. Our results reveal that genome maintenance programs of postreplicative cells, including DDR, are regulated by the overall level of Cdk activity and not by specific Cdks.

scholarly journals The Licensing Factor Cdt1 Links Cell Cycle Progression to the DNA Damage Response

2020 ◽  
Vol 40 (5) ◽  
pp. 2449-2456
Author(s):  
ALEXANDRA KANELLOU ◽  
NICKOLAOS NIKIFOROS GIAKOUMAKIS ◽  
ANDREAS PANAGOPOULOS ◽  
SPYRIDON CHAMPERIS TSANIRAS ◽  
ZOI LYGEROU
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Damage Response ◽  
Licensing Factor

scholarly journals Cellular responses to a prolonged delay in mitosis are determined by a DNA damage response controlled by Bcl-2 family proteins

Open Biology ◽  
2015 ◽  
Vol 5 (3) ◽  
pp. 140156 ◽  
Author(s):  
Didier J. Colin ◽  
Karolina O. Hain ◽  
Lindsey A. Allan ◽  
Paul R. Clarke
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Protein Kinases ◽  
Cell Fate ◽  
Dna Damage Response ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Anti Cancer ◽  
Damage Response ◽  
Microtubule Poisons

Anti-cancer drugs that disrupt mitosis inhibit cell proliferation and induce apoptosis, although the mechanisms of these responses are poorly understood. Here, we characterize a mitotic stress response that determines cell fate in response to microtubule poisons. We show that mitotic arrest induced by these drugs produces a temporally controlled DNA damage response (DDR) characterized by the caspase-dependent formation of γH2AX foci in non-apoptotic cells. Following exit from a delayed mitosis, this initial response results in activation of DDR protein kinases, phosphorylation of the tumour suppressor p53 and a delay in subsequent cell cycle progression. We show that this response is controlled by Mcl-1, a regulator of caspase activation that becomes degraded during mitotic arrest. Chemical inhibition of Mcl-1 and the related proteins Bcl-2 and Bcl-x L by a BH3 mimetic enhances the mitotic DDR, promotes p53 activation and inhibits subsequent cell cycle progression. We also show that inhibitors of DDR protein kinases as well as BH3 mimetics promote apoptosis synergistically with taxol (paclitaxel) in a variety of cancer cell lines. Our work demonstrates the role of mitotic DNA damage responses in determining cell fate in response to microtubule poisons and BH3 mimetics, providing a rationale for anti-cancer combination chemotherapies.

scholarly journals Zfp423, a Joubert syndrome gene, is a domain-specific regulator of cell cycle progression, DNA damage response and Purkinje cell development in the cerebellar primordium

2017 ◽  
Author(s):  
Filippo Casonil ◽  
Laura Crocil ◽  
Camilla Bosonel ◽  
Roberta D’Ambrosio ◽  
Aurora Badaloni ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Neural Development ◽  
Cell Cycle Progression ◽  
Ventricular Zone ◽  
Joubert Syndrome ◽  
Cycle Progression ◽  
Domain Specific ◽  
Damage Response

ABSTRACTNeurogenesis is a tightly regulated process whose success depends on the ability to balance the expansion/maintenance of an undifferentiated neural progenitor pool with the precisely timed birth of sequential generations of neurons. The Zfp423 gene encodes a 30-Zn-finger transcription factor (TF) that acts as a scaffold in the assembly of complex transcriptional and cellular machineries regulating neural development. While null mutants for Zfp423 feature a severe cerebellar hypoplasia, the underlying mechanism is only partially characterized. Mutations of the human ortholog ZNF423 have been identified in patients carrying cerebellar vermis hypoplasia (CVH) or Joubert Syndrome (JS), associated with other signs of classical ciliopathy outside the central nervous system (CNS). ZNF423 also plays a role in the DNA damage response (DDR). To further characterize the role of ZFP423 in cerebellar neurogenesis, with a focus on Purkinje cells (PC) development, we analyzed two previously undescribed mutant mouse lines carrying allelic in-frame deletions of the corresponding gene, selectively affecting two functionally characterized protein-protein interaction domains, affecting zinc (Zn) fingers 9-20 or 28-30. Some phenotypic defects are allele specific: Zfp423Δ9-20/Δ9-20 mutants exhibit a depletion of the OLIG2+ PC progenitor pool in the cerebellar ventricular zone (VZ). In these mutants, M-phase progenitors display changes in spindle orientation indicative of a precocious switch from symmetric to asymmetric cell division. Conversely, the Zfp423Δ28-30/Δ28-30 primordium displays a sharp decrease in the expression of PC differentiation markers, including CORL2, despite an abundance of cycling PC progenitors. Moreover, and importantly, in both mutants VZ progenitor cell cycle progression is remarkably affected, and factors involved in the DDR are substantially upregulated in the VZ and in postmitotic precursors alike. Our in vivo evidence sheds light on the domain-specific roles played by ZFP423 in different aspects of PC progenitor development, and at the same time supports the emerging notion that an impaired DNA damage response may be a key factor in the pathogenesis of JS and other ciliopathies.

scholarly journals ATM and ATR Influence Meiotic Crossover Formation Through Antagonistic and Overlapping Functions inC. elegans

2019 ◽  
Author(s):  
Wei Li ◽  
Judith Yanowitz
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Cell Cycle Progression ◽  
Molecular Networks ◽  
Ataxia Telangiectasia Mutated ◽  
Cycle Progression ◽  
Strand Breaks ◽  
Regulatory Processes ◽  
Damage Response ◽  
Repair Template

ABSTRACTDuring meiosis, formation of double-strand breaks (DSBs) and repair by homologous recombination between homologs creates crossovers (COs) that facilitate chromosome segregation. CO formation is tightly regulated to ensure the integrity of this process. The DNA damage response kinases, Ataxia-telangiectasia mutated (ATM) and RAD3-related (ATR) have emerged as key regulators of CO formation in yeast, flies, and mice, influencing DSB formation, repair pathway choice, and cell cycle progression. The molecular networks that ATM and ATR influence during meiosis are still being resolved in other organisms. Here we show thatCaenorhabditis elegansATM and ATR homologs, ATM-1 and ATL-1 respectively, act at multiple steps in CO formation to ultimately ensure that COs are formed on all chromosomes. We show a role for ATM-1 in regulating the choice of repair template, biasing use of the homologous chromosome instead of the sister chromatid. Our data suggests a model in which ATM-1 and ATL-1 have antagonistic roles in very early repair processing, but are redundantly required for accumulation of the RAD-51 recombinase at DSB sites. We propose that these features of ATM-1 and ATL-1 ensure both CO formation on all chromosomes and accurate repair of additional DSBs.Article SummaryCrossovers formed during meiosis connect homologs and properly align them for cell division. The central importance of crossovers is underscored by the existence of extensive regulatory processes that ensures the proper execution of these events. This paper explores the evolutionary conserved roles of the central DNA damage response kinases, ATM and ATR, in crossover formation. The authors show that these kinases function together as rheostats to promote timely formation of crossovers on all chromosomes but to limit extensive DNA damage. This work provides a platform for identifying conserved meiotic targets of ATM and ATR that affect fertility across species.

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