PF215 THE ROLE OF GROWTH FACTOR INDEPENDENCE 1 (GFI1) IN GENOME STABILITY, DNA REPAIR AND LEUKEMIA GENOMIC EVOLUTION

The human body is a complex structure of cells, which are exposed to many types of stress. Cells must utilize various mechanisms to protect their DNA from damage caused by metabolic and external sources to maintain genomic integrity and homeostasis and to prevent the development of cancer. DNA damage inevitably occurs regardless of physiological or abnormal conditions. In response to DNA damage, signaling pathways are activated to repair the damaged DNA or to induce cell apoptosis. During the process, posttranslational modifications (PTMs) can be used to modulate enzymatic activities and regulate protein stability, protein localization, and protein-protein interactions. Thus, PTMs in DNA repair should be studied. In this review, we will focus on the current understanding of the phosphorylation, poly(ADP-ribosyl)ation, ubiquitination, SUMOylation, acetylation, and methylation of six typical PTMs and summarize PTMs of the key proteins in DNA repair, providing important insight into the role of PTMs in the maintenance of genome stability and contributing to reveal new and selective therapeutic approaches to target cancers.

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Role of the Insulin-Like Growth Factor I/Insulin Receptor Substrate 1 Axis in Rad51 Trafficking and DNA Repair by Homologous Recombination

Molecular and Cellular Biology ◽

10.1128/mcb.23.21.7510-7524.2003 ◽

2003 ◽

Vol 23 (21) ◽

pp. 7510-7524 ◽

Cited By ~ 76

Author(s):

Joanna Trojanek ◽

Thu Ho ◽

Luis Del Valle ◽

Michal Nowicki ◽

Jin Ying Wang ◽

...

Keyword(s):

Dna Repair ◽

Growth Factor ◽

Homologous Recombination ◽

Insulin Receptor ◽

Insulin Receptor Substrate ◽

Insulin Like Growth Factor ◽

Insulin Receptor Substrate 1 ◽

Factor I ◽

Igf I

ABSTRACT The receptor for insulin-like growth factor I (IGF-IR) controls normal and pathological growth of cells. DNA repair pathways represent an unexplored target through which the IGF-IR signaling system might support pathological growth leading to cellular transformation. However, this study demonstrates that IGF-I stimulation supports homologous recombination-directed DNA repair (HRR). This effect involves an interaction between Rad51 and the major IGF-IR signaling molecule, insulin receptor substrate 1 (IRS-1). The binding occurs within the cytoplasm, engages the N-terminal domain of IRS-1, and is attenuated by IGF-I-mediated IRS-1 tyrosine phosphorylation. In the absence of IGF-I stimulation, or if mutated IGF-IR fails to phosphorylate IRS-1, localization of Rad51 to the sites of damaged DNA is diminished. These results point to a direct role of IRS-1 in HRR and suggest a novel role for the IGF-IR/IRS-1 axis in supporting the stability of the genome.

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Sister chromatid cohesion and genome stability in vertebrate cells

Biochemical Society Transactions ◽

10.1042/bst0310263 ◽

2003 ◽

Vol 31 (1) ◽

pp. 263-265 ◽

Cited By ~ 20

Author(s):

C. Morrison ◽

P. Vagnarelli ◽

E. Sonoda ◽

S. Takeda ◽

W.C. Earnshaw

Keyword(s):

Dna Repair ◽

Chromosome Segregation ◽

Sister Chromatid ◽

Genome Stability ◽

Sister Chromatid Cohesion ◽

Spindle Poles ◽

Chromatid Cohesion ◽

Chromosomal Passenger ◽

Passenger Protein

For successful eukaryotic mitosis, sister chromatid pairs remain linked after replication until their kinetochores have been attached to opposite spindle poles by microtubules. This linkage is broken at the metaphase–anaphase transition and the sisters separate. In budding yeast, this sister chromatid cohesion requires a multi-protein complex called cohesin. A key component of cohesin is Scc1/Mcd1 (Rad21 in fission yeast). Disruption of the chicken orthologue of Scc1 by gene targeting in DT40 cells causes premature sister chromatid separation. Cohesion between sister chromatids is likely to provide a substrate for post-replicative DNA repair by homologous recombination. In keeping with this role of cohesion, Scc1 mutants also show defects in the repair of spontaneous and induced DNA damage. Scc1-deficient cells frequently fail to complete metaphase chromosome alignment and show chromosome segregation defects, suggesting aberrant kinetochore function. Consistent with this, the chromosomal passenger protein, INCENP (inner centromere protein) fails to localize to centromeres. Survivin, another passenger protein and one which interacts with INCENP, also fails to localize to centromeres in Scc1-deficient cells. These results show that cohesin maintains genomic stability by ensuring appropriate DNA repair and equal chromosome segregation at mitosis.

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N6-Methyladenosine, DNA Repair, and Genome Stability

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.645823 ◽

2021 ◽

Vol 8 ◽

Author(s):

Fei Qu ◽

Pawlos S. Tsegay ◽

Yuan Liu

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Cellular Response ◽

Genome Stability ◽

Fine Tuning ◽

Genome Integrity ◽

Cell Renewal ◽

The Novel ◽

Cellular Sensitivity

N6-methyladenosine (m6A) modification in mRNAs and non-coding RNAs is a newly identified epitranscriptomic mark. It provides a fine-tuning of gene expression to serve as a cellular response to endogenous and exogenous stimuli. m6A is involved in regulating genes in multiple cellular pathways and functions, including circadian rhythm, cell renewal, differentiation, neurogenesis, immunity, among others. Disruption of m6A regulation is associated with cancer, obesity, and immune diseases. Recent studies have shown that m6A can be induced by oxidative stress and DNA damage to regulate DNA repair. Also, deficiency of the m6A eraser, fat mass obesity-associated protein (FTO) can increase cellular sensitivity to genotoxicants. These findings shed light on the novel roles of m6A in modulating DNA repair and genome integrity and stability through responding to DNA damage. In this mini-review, we discuss recent progress in the understanding of a unique role of m6As in mRNAs, lncRNAs, and microRNAs in DNA damage response and regulation of DNA repair and genome integrity and instability.

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Role of Deubiquitinating Enzymes in DNA Repair

Molecular and Cellular Biology ◽

10.1128/mcb.00847-15 ◽

2015 ◽

Vol 36 (4) ◽

pp. 524-544 ◽

Cited By ~ 34

Author(s):

Younghoon Kee ◽

Tony T Huang

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Mammalian Cells ◽

Genome Stability ◽

Regulatory Mechanisms ◽

Deubiquitinating Enzymes ◽

Genome Maintenance ◽

Dna Damage Signaling ◽

Damage Response

Both proteolytic and nonproteolytic functions of ubiquitination are essential regulatory mechanisms for promoting DNA repair and the DNA damage response in mammalian cells. Deubiquitinating enzymes (DUBs) have emerged as key players in the maintenance of genome stability. In this minireview, we discuss the recent findings on human DUBs that participate in genome maintenance, with a focus on the role of DUBs in the modulation of DNA repair and DNA damage signaling.

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Regulation of the Fanconi Anemia DNA Repair Pathway by Phosphorylation and Monoubiquitination

Genes ◽

10.3390/genes12111763 ◽

2021 ◽

Vol 12 (11) ◽

pp. 1763

Author(s):

Masamichi Ishiai

Keyword(s):

Dna Repair ◽

Fanconi Anemia ◽

Genome Stability ◽

Short Review ◽

Repair Pathway ◽

Binding Partner ◽

Interstrand Crosslinks ◽

Pathway Activation ◽

Dna Interstrand Crosslinks

The Fanconi anemia (FA) DNA repair pathway coordinates a faithful repair mechanism for stalled DNA replication forks caused by factors such as DNA interstrand crosslinks (ICLs) or replication stress. An important role of FA pathway activation is initiated by monoubiquitination of FANCD2 and its binding partner of FANCI, which is regulated by the ATM-related kinase, ATR. Therefore, regulation of the FA pathway is a good example of the contribution of ATR to genome stability. In this short review, we summarize the knowledge accumulated over the years regarding how the FA pathway is activated via phosphorylation and monoubiquitination.

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Aberrant repair initiated by the adenine-DNA glycosylase does not play a role in UV-induced mutagenesis in Escherichia coli

PeerJ ◽

10.7717/peerj.6029 ◽

2018 ◽

Vol 6 ◽

pp. e6029 ◽

Cited By ~ 2

Author(s):

Caroline Zutterling ◽

Aibek Mursalimov ◽

Ibtissam Talhaoui ◽

Zhanat Koshenov ◽

Zhiger Akishev ◽

...

Keyword(s):

Escherichia Coli ◽

Dna Damage ◽

Dna Repair ◽

Uv Irradiation ◽

Genome Stability ◽

Dna Duplexes ◽

E Coli ◽

Dna Strands ◽

Induced Mutagenesis

Background DNA repair is essential to counteract damage to DNA induced by endo- and exogenous factors, to maintain genome stability. However, challenges to the faithful discrimination between damaged and non-damaged DNA strands do exist, such as mismatched pairs between two regular bases resulting from spontaneous deamination of 5-methylcytosine or DNA polymerase errors during replication. To counteract these mutagenic threats to genome stability, cells evolved the mismatch-specific DNA glycosylases that can recognize and remove regular DNA bases in the mismatched DNA duplexes. The Escherichia coli adenine-DNA glycosylase (MutY/MicA) protects cells against oxidative stress-induced mutagenesis by removing adenine which is mispaired with 7,8-dihydro-8-oxoguanine (8oxoG) in the base excision repair pathway. However, MutY does not discriminate between template and newly synthesized DNA strands. Therefore the ability to remove A from 8oxoG•A mispair, which is generated via misincorporation of an 8-oxo-2′-deoxyguanosine-5′-triphosphate precursor during DNA replication and in which A is the template base, can induce A•T→C•G transversions. Furthermore, it has been demonstrated that human MUTYH, homologous to the bacterial MutY, might be involved in the aberrant processing of ultraviolet (UV) induced DNA damage. Methods Here, we investigated the role of MutY in UV-induced mutagenesis in E. coli. MutY was probed on DNA duplexes containing cyclobutane pyrimidine dimers (CPD) and pyrimidine (6–4) pyrimidone photoproduct (6–4PP). UV irradiation of E. coli induces Save Our Souls (SOS) response characterized by increased production of DNA repair enzymes and mutagenesis. To study the role of MutY in vivo, the mutation frequencies to rifampicin-resistant (RifR) after UV irradiation of wild type and mutant E. coli strains were measured. Results We demonstrated that MutY does not excise Adenine when it is paired with CPD and 6–4PP adducts in duplex DNA. At the same time, MutY excises Adenine in A•G and A•8oxoG mispairs. Interestingly, E. coli mutY strains, which have elevated spontaneous mutation rate, exhibited low mutational induction after UV exposure as compared to MutY-proficient strains. However, sequence analysis of RifR mutants revealed that the frequencies of C→T transitions dramatically increased after UV irradiation in both MutY-proficient and -deficient E. coli strains. Discussion These findings indicate that the bacterial MutY is not involved in the aberrant DNA repair of UV-induced DNA damage.

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Histone marks: repairing DNA breaks within the context of chromatin

Biochemical Society Transactions ◽

10.1042/bst20110747 ◽

2012 ◽

Vol 40 (2) ◽

pp. 370-376 ◽

Cited By ~ 62

Author(s):

Kyle M. Miller ◽

Stephen P. Jackson

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Genome Stability ◽

Nuclear Dna ◽

Dna Lesions ◽

Dna Breaks ◽

Strand Breaks ◽

Dna Dsbs

Inherited or acquired defects in detecting, signalling or repairing DNA damage are associated with various human pathologies, including immunodeficiencies, neurodegenerative diseases and various forms of cancer. Nuclear DNA is packaged into chromatin and therefore the true in vivo substrate of damaged DNA occurs within the context of chromatin. Our work aims to decipher the mechanisms by which cells detect DNA damage and signal its presence to the DNA-repair and cell-cycle machineries. In particular, much of our work has focused on DNA DSBs (double-strand breaks) that are generated by ionizing radiation and radiomimetic chemicals, and which can also arise when the DNA replication apparatus encounters other DNA lesions. In the present review, we describe some of our recent work, as well as the work of other laboratories, that has identified new chromatin proteins that mediate DSB responses, control SDB processing or modulate chromatin structure at DNA-damage sites. We also aim to survey several recent advances in the field that have contributed to our understanding of how particular histone modifications and involved in DNA repair. It is our hope that by understanding the role of chromatin and its modifications in promoting DNA repair and genome stability, this knowledge will provide opportunities for developing novel classes of drugs to treat human diseases, including cancer.

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