The role and clinical significance of DNA damage response and repair pathways in primary brain tumors

Besides the nuclear genome, plants possess two small extra chromosomal genomes in mitochondria and chloroplast, respectively, which contribute a small fraction of the organelles’ proteome. Both mitochondrial and chloroplast DNA have originated endosymbiotically and most of their prokaryotic genes were either lost or transferred to the nuclear genome through endosymbiotic gene transfer during the course of evolution. Due to their immobile nature, plant nuclear and organellar genomes face continuous threat from diverse exogenous agents as well as some reactive by-products or intermediates released from various endogenous metabolic pathways. These factors eventually affect the overall plant growth and development and finally productivity. The detailed mechanism of DNA damage response and repair following accumulation of various forms of DNA lesions, including single and double-strand breaks (SSBs and DSBs) have been well documented for the nuclear genome and now it has been extended to the organelles also. Recently, it has been shown that both mitochondria and chloroplast possess a counterpart of most of the nuclear DNA damage repair pathways and share remarkable similarities with different damage repair proteins present in the nucleus. Among various repair pathways, homologous recombination (HR) is crucial for the repair as well as the evolution of organellar genomes. Along with the repair pathways, various other factors, such as the MSH1 and WHIRLY family proteins, WHY1, WHY2, and WHY3 are also known to be involved in maintaining low mutation rates and structural integrity of mitochondrial and chloroplast genome. SOG1, the central regulator in DNA damage response in plants, has also been found to mediate endoreduplication and cell-cycle progression through chloroplast to nucleus retrograde signaling in response to chloroplast genome instability. Various proteins associated with the maintenance of genome stability are targeted to both nuclear and organellar compartments, establishing communication between organelles as well as organelles and nucleus. Therefore, understanding the mechanism of DNA damage repair and inter compartmental crosstalk mechanism in various sub-cellular organelles following induction of DNA damage and identification of key components of such signaling cascades may eventually be translated into strategies for crop improvement under abiotic and genotoxic stress conditions. This review mainly highlights the current understanding as well as the importance of different aspects of organelle genome maintenance mechanisms in higher plants.

Download Full-text

The heterogeneity of the DNA damage response landscape determines patient outcomes in ovarian cancer

10.1101/2021.08.03.454868 ◽

2021 ◽

Author(s):

Thomas Walker ◽

Zahra Faraahi ◽

marcus price ◽

Amy Hawarden ◽

Catlin Waddell ◽

...

Keyword(s):

Ovarian Cancer ◽

Dna Damage ◽

Dna Damage Response ◽

Ex Vivo ◽

Single Strand ◽

Cellular Growth ◽

Response To Chemotherapy ◽

Damage Response ◽

Repair Pathways ◽

Non Homologous End Joining

Defective DNA damage response (DDR) pathways allow cancer cells to accrue genomic aberrations and evade normal cellular growth checkpoints. Defective DDR also determines response to chemotherapy. However, the interaction and overlap between the two double strand repair pathways and the three single strand repair pathways is complex, and has remained poorly understood. Here we show that, in ovarian cancer, a disease hallmarked by chromosomal instability, explant cultures show a range of DDR abrogation patterns. Defective homologous recombination (HR) and non-homologous end joining (NHEJ) are near mutually exclusive with HR deficient (HRD) cells showing increased abrogation of the single strand repair pathways compared to NHEJ defective cells. When combined with global markers of DNA damage, including mitochondrial membrane functionality and reactive oxygen species burden, the pattern of DDR abrogation allows the construction of DDR signatures which are predictive of both ex vivo cytotoxicity, and more importantly, patient outcome.

Download Full-text

Molecular Pathways: Emergence of Protein Kinase CK2 (CSNK2) as a Potential Target to Inhibit Survival and DNA Damage Response and Repair Pathways in Cancer Cells

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-15-1314 ◽

2016 ◽

Vol 22 (12) ◽

pp. 2840-2847 ◽

Cited By ~ 33

Author(s):

Adam J. Rabalski ◽

Laszlo Gyenis ◽

David W. Litchfield

Keyword(s):

Dna Damage ◽

Protein Kinase ◽

Cancer Cells ◽

Dna Damage Response ◽

Protein Kinase Ck2 ◽

Molecular Pathways ◽

Potential Target ◽

Damage Response ◽

Repair Pathways ◽

Kinase Ck2

Download Full-text

Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress

Cellular and Molecular Life Sciences ◽

10.1007/s00018-014-1666-4 ◽

2014 ◽

Vol 71 (20) ◽

pp. 3951-3967 ◽

Cited By ~ 98

Author(s):

Shan Yan ◽

Melanie Sorrell ◽

Zachary Berman

Keyword(s):

Oxidative Stress ◽

Dna Damage ◽

Dna Repair ◽

Dna Damage Response ◽

Damage Response ◽

Repair Pathways

Download Full-text

Genetic instability

Oxford Textbook of Oncology ◽

10.1093/med/9780199656103.003.0008 ◽

2016 ◽

pp. 72-81

Author(s):

Jennifer Wilding ◽

Walter Bodmer

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Genetic Instability ◽

Molecular Basis ◽

Driving Force ◽

Germline Mutations ◽

Absolute Requirement ◽

Damage Response ◽

Repair Pathways ◽

Chromosome Level

Most cancers are thought to exhibit some form of genetic instability, which can either be at the nucleotide or chromosome level. It is tempting to speculate that because genetic instability accelerates the rate of accumulation of mutations, it would act as a necessary driving force for the development and progression of cancer, and there has been much debate as to whether there is an absolute requirement for genetic instability during tumorigenesis. Although the mechanism of the acquired genetic instability is clear in many germline cancer-predisposing syndromes, the molecular basis for genetic instability in sporadic cancers remains unclear. This chapter will give a very brief summary of the main features of the major DNA damage response and repair pathways, the germline mutations in genes within these pathways which predispose to cancers, and an overview of some of the possible mechanisms through which sporadic cancers may become genetically unstable.

Download Full-text

Synthetic Lethality In CLL With DNA Damage Response Defect By Targeting ATR Pathway

Blood ◽

10.1182/blood.v122.21.120.120 ◽

2013 ◽

Vol 122 (21) ◽

pp. 120-120

Author(s):

Tatjana Stankovic ◽

Davies Nicholas ◽

Marwan Kwok ◽

Edward Smith ◽

Eliot Yates ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Dna Damage Response ◽

Synthetic Lethality ◽

Double Strand Breaks ◽

Dna Double Strand Breaks ◽

Single Strand Break ◽

Strand Breaks ◽

Damage Response ◽

Repair Pathways

Abstract Ataxia Telangiectasia Mutated (ATM) protein coordinates responses to DNA double strand breaks (DSBs) and the ATM-null status caused by biallelic ATM gene inactivation in chronic lymphocytic leukemia (CLL) results in resistance to p53-dependent apoptosis. Accordingly, alternative strategies to target ATM-null CLL are needed. ATM is a serine/threonine protein kinase that synchronises rapid DNA damage response (DDR) to DNA double strand breaks (DSBs) with activation of cell cycle checkpoints, DNA repair and apoptosis via p53 activation. ATM-null cells are defective in a type of DSB repair that involves homologous recombination and rely on co-operating and compensatory DNA repair pathways for their survival. Therefore, inhibition of DNA repair pathways to which CLL cells with loss of ATM signalling become addicted could provide ‘synthetic lethality’ and induce tumour specific killing. Indeed, we have recently shown that inhibition of a single strand break protein PARP induces differential killing of ATM-null CLL tumours. Here we expand the concept of synthetic lethality in ATM-null CLL and address the question of whether ATM-null deficient CLL cells can be targeted by inhibition of the ATR protein that governs responses to post-replicative damage and co-operates with ATM. First, we addressed the status of the ATR pathway in primary CLL cells and consistent with previous findings we observed that initiation of cell cycling is required for both ATR upregulation and activation of ATR target Chk1 in response to replicating stress inducing agent hydroxyurea. We then proceeded with testing viability of the isogenic CLL cell line CII, with and without stable ATM knock down, in the presence or absence of increasing doses of ATR inhibitor AZD6738. We observed a uniform loss of cellular viability in the presence of 1 or 3 μM of inhibitor in ATM-null cells but not in the ATM-wt counterpart. Similar observation was made in primary CLL cells initiated to cycle in the presence of stimulatory oligonucleotide-ODN2006/IL2 support. To confirm the cytotoxic effect of AZD6738 in vivo we used an ATM null primary CLL xenograft model. Representative primary CLL tumour cells with 15% bialleic ATM inactivation, as assessed by percentage of 11q deletion and allelic frequency of ATM mutation 4220T>C, was engrafted in the presence of activated autologous T lymphocytes into 10 NOG mice. Upon detection of engraftment in peripheral blood, animals were treated by oral administration of either AZD6738 (50mg/kg) or vehicle alone over a 2 week period, and tumour load measured by FACS analysis of CD45+ CD19+ human cells in infiltrated spleens. We observed a reduction in tumour cell numbers in AZD6738-treated compared to vehicle-treated spleens and current investigations are underway to determine whether this difference can be attributed to the selective disappearance of CLL population with biallelic ATM loss. We suggest that targeting ATR pathway provides an attractive approach for selective killing of ATM-null CLL cells and that this approach should be considered as a future therapeutic strategy for this CLL subtype. Disclosures: Off Label Use: ATR inhibitor AZD6738 targets ATM-null phenotype inducing synthetic lethality. Jeff:AstraZeneca Pharmaceuticals: Employment, Patents & Royalties. Lau:AstraZeneca Pharmaceuticals: Employment.

Download Full-text

Function and Interactions of ERCC1-XPF in DNA Damage Response

Molecules ◽

10.3390/molecules23123205 ◽

2018 ◽

Vol 23 (12) ◽

pp. 3205 ◽

Cited By ~ 15

Author(s):

Maryam Faridounnia ◽

Gert Folkers ◽

Rolf Boelens

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Excision Repair ◽

Strand Break ◽

Response Network ◽

Nucleotide Excision ◽

Damage Response ◽

Human Disorders ◽

Heterodimeric Complex ◽

Repair Pathways

Numerous proteins are involved in the multiple pathways of the DNA damage response network and play a key role to protect the genome from the wide variety of damages that can occur to DNA. An example of this is the structure-specific endonuclease ERCC1-XPF. This heterodimeric complex is in particular involved in nucleotide excision repair (NER), but also in double strand break repair and interstrand cross-link repair pathways. Here we review the function of ERCC1-XPF in various DNA repair pathways and discuss human disorders associated with ERCC1-XPF deficiency. We also overview our molecular and structural understanding of XPF-ERCC1.

Download Full-text