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DNA Damage Response, an Update

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (25 June 2023) | Viewed by 15886

Special Issue Editor

Department of Biology, University of Rome Tor Vergata, Via Della Ricerca Scientifica, 00133 Rome, Italy
Interests: molecular biology; post translational modifications; phosphorylation; tyrosine kinases; cell signaling pathways
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

DNA damage response (DDR) represents the way cells react to preserve genome integrity. DNA breaks can arise either spontaneously, during replication, or in response to exogenous compounds. Biochemical characterization of signaling events underlying the DDR has allowed the design and the development of specific inhibitors. Nonetheless, their potential use in monotherapy strategies or in combination with radiotherapy or chemotherapy against cancer cells has not given the expected results. This may be due to the fact that DDR is controlled in a redundant way through intricate and complex mechanisms. These mechanisms involve either post-translational modifications on chromatin, expression of small regulatory RNAs, or changes in chromatin architecture. In this topic, we invite the submission of original research papers and review articles that cover any aspect of DDR. Special emphasis will be given to the emerging crosstalk between DDR and other cellular signaling paths, occurring either in physiological or pathological conditions.

Dr. Stefania Gonfloni
Guest Editor

Manuscript Submission Information

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Keywords

  • DNA damage
  • Cellular differentiation
  • Autophagy
  • Metabolic disease
  • Mitochondrial dysfunction

Published Papers (7 papers)

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Research

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19 pages, 4291 KiB  
Article
DNA Damage Response−Related Proteins Are Prognostic for Outcome in Both Adult and Pediatric Acute Myelogenous Leukemia Patients: Samples from Adults and from Children Enrolled in a Children’s Oncology Group Study
by Stefan E. Hubner, Eduardo S. de Camargo Magalhães, Fieke W. Hoff, Brandon D. Brown, Yihua Qiu, Terzah M. Horton and Steven M. Kornblau
Int. J. Mol. Sci. 2023, 24(6), 5898; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24065898 - 20 Mar 2023
Viewed by 1458
Abstract
The survival of malignant leukemic cells is dependent on DNA damage repair (DDR) signaling. Reverse Phase Protein Array (RPPA) data sets were assembled using diagnostic samples from 810 adult and 500 pediatric acute myelogenous leukemia (AML) patients and were probed with 412 and [...] Read more.
The survival of malignant leukemic cells is dependent on DNA damage repair (DDR) signaling. Reverse Phase Protein Array (RPPA) data sets were assembled using diagnostic samples from 810 adult and 500 pediatric acute myelogenous leukemia (AML) patients and were probed with 412 and 296 strictly validated antibodies, respectively, including those detecting the expression of proteins directly involved in DDR. Unbiased hierarchical clustering identified strong recurrent DDR protein expression patterns in both adult and pediatric AML. Globally, DDR expression was associated with gene mutational statuses and was prognostic for outcomes including overall survival (OS), relapse rate, and remission duration (RD). In adult patients, seven DDR proteins were individually prognostic for either RD or OS. When DDR proteins were analyzed together with DDR−related proteins operating in diverse cellular signaling pathways, these expanded groupings were also highly prognostic for OS. Analysis of patients treated with either conventional chemotherapy or venetoclax combined with a hypomethylating agent revealed protein clusters that differentially predicted favorable from unfavorable prognoses within each therapy cohort. Collectively, this investigation provides insight into variable DDR pathway activation in AML and may help direct future individualized DDR−targeted therapies in AML patients. Full article
(This article belongs to the Special Issue DNA Damage Response, an Update)
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13 pages, 3676 KiB  
Article
Prognostication of DNA Damage Response Protein Expression Patterns in Chronic Lymphocytic Leukemia
by Ti’ara L. Griffen, Fieke W. Hoff, Yihua Qiu, Jan Burger, William Wierda and Steven M. Kornblau
Int. J. Mol. Sci. 2023, 24(6), 5481; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24065481 - 13 Mar 2023
Viewed by 1168
Abstract
Proteomic DNA Damage Repair (DDR) expression patterns in Chronic Lymphocytic Leukemia were characterized by quantifying and clustering 24 total and phosphorylated DDR proteins. Overall, three protein expression patterns (C1-C3) were identified and were associated as an independent predictor of distinct patient overall survival [...] Read more.
Proteomic DNA Damage Repair (DDR) expression patterns in Chronic Lymphocytic Leukemia were characterized by quantifying and clustering 24 total and phosphorylated DDR proteins. Overall, three protein expression patterns (C1-C3) were identified and were associated as an independent predictor of distinct patient overall survival outcomes. Patients within clusters C1 and C2 had poorer survival outcomes and responses to fludarabine, cyclophosphamide, and rituxan chemotherapy compared to patients within cluster C3. However, DDR protein expression patterns were not prognostic in more modern therapies with BCL2 inhibitors or a BTK/PI3K inhibitor. Individually, nine of the DDR proteins were prognostic for predicting overall survival and/or time to first treatment. When looking for other proteins that may be associated with or influenced by DDR expression patterns, our differential expression analysis found that cell cycle and adhesion proteins were lower in clusters compared to normal CD19 controls. In addition, cluster C3 had a lower expression of MAPK proteins compared to the poor prognostic patient clusters thus implying a potential regulatory connection between adhesion, cell cycle, MAPK, and DDR signaling in CLL. Thus, assessing the proteomic expression of DNA damage proteins in CLL provided novel insights for deciphering influences on patient outcomes and expanded our understanding of the potential complexities and effects of DDR cell signaling. Full article
(This article belongs to the Special Issue DNA Damage Response, an Update)
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11 pages, 2867 KiB  
Article
Reverse Phase Protein Array Profiling Identifies Recurrent Protein Expression Patterns of DNA Damage-Related Proteins across Acute and Chronic Leukemia: Samples from Adults and the Children’s Oncology Group
by Fieke W. Hoff, Ti’ara L. Griffen, Brandon D. Brown, Terzah M. Horton, Jan Burger, William Wierda, Stefan E. Hubner, Yihua Qiu and Steven M. Kornblau
Int. J. Mol. Sci. 2023, 24(6), 5460; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24065460 - 13 Mar 2023
Viewed by 1391
Abstract
DNA damage response (DNADR) recognition and repair (DDR) pathways affect carcinogenesis and therapy responsiveness in cancers, including leukemia. We measured protein expression levels of 16 DNADR and DDR proteins using the Reverse Phase Protein Array methodology in acute myeloid (AML) (n = [...] Read more.
DNA damage response (DNADR) recognition and repair (DDR) pathways affect carcinogenesis and therapy responsiveness in cancers, including leukemia. We measured protein expression levels of 16 DNADR and DDR proteins using the Reverse Phase Protein Array methodology in acute myeloid (AML) (n = 1310), T-cell acute lymphoblastic leukemia (T-ALL) (n = 361) and chronic lymphocytic leukemia (CLL) (n = 795) cases. Clustering analysis identified five protein expression clusters; three were unique compared to normal CD34+ cells. Individual protein expression differed by disease for 14/16 proteins, with five highest in CLL and nine in T-ALL, and by age in T-ALL and AML (six and eleven proteins, respectively), but not CLL (n = 0). Most (96%) of the CLL cases clustered in one cluster; the other 4% were characterized by higher frequencies of deletion 13q and 17p, and fared poorly (p < 0.001). T-ALL predominated in C1 and AML in C5, but both occurred in all four acute-dominated clusters. Protein clusters showed similar implications for survival and remission duration in pediatric and adult T-ALL and AML populations, with C5 doing best in all. In summary, DNADR and DDR protein expression was abnormal in leukemia and formed recurrent clusters that were shared across the leukemias with shared prognostic implications across diseases, and individual proteins showed age- and disease-related differences. Full article
(This article belongs to the Special Issue DNA Damage Response, an Update)
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Review

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10 pages, 1005 KiB  
Review
DNA Damage Stress Response and Follicle Activation: Signaling Routes of Mammalian Ovarian Reserve
by Stefania Gonfloni, Carla Jodice, Bianca Gustavino and Elvia Valentini
Int. J. Mol. Sci. 2022, 23(22), 14379; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232214379 - 19 Nov 2022
Cited by 2 | Viewed by 1868
Abstract
Chemotherapy regimens and radiotherapy are common strategies to fight cancer. In women, these therapies may cause side effects such as premature ovarian insufficiency (POI) and infertility. Clinical strategies to protect the ovarian reserve from the lethal effect of cancer therapies needs better understanding [...] Read more.
Chemotherapy regimens and radiotherapy are common strategies to fight cancer. In women, these therapies may cause side effects such as premature ovarian insufficiency (POI) and infertility. Clinical strategies to protect the ovarian reserve from the lethal effect of cancer therapies needs better understanding of the mechanisms underlying iatrogenic loss of follicle reserve. Recent reports demonstrate a critical role for p53 and CHK2 in the oocyte response to different DNA stressors, which are commonly used to treat cancer. Here we review the molecular mechanisms underlying the DNA damage stress response (DDR) and discuss crosstalk between DDR and signaling pathways implicated in primordial follicle activation. Full article
(This article belongs to the Special Issue DNA Damage Response, an Update)
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14 pages, 1664 KiB  
Review
Focal Point of Fanconi Anemia Signaling
by Sudong Zhan, Jolene Siu, Zhanwei Wang, Herbert Yu, Tedros Bezabeh, Youping Deng, Wei Du and Peiwen Fei
Int. J. Mol. Sci. 2021, 22(23), 12976; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222312976 - 30 Nov 2021
Cited by 6 | Viewed by 2497
Abstract
Among human genetic diseases, Fanconi Anemia (FA) tops all with its largest number of health complications in nearly all human organ systems, suggesting the significant roles played by FA genes in the maintenance of human health. With the accumulated research on FA, the [...] Read more.
Among human genetic diseases, Fanconi Anemia (FA) tops all with its largest number of health complications in nearly all human organ systems, suggesting the significant roles played by FA genes in the maintenance of human health. With the accumulated research on FA, the encoded protein products by FA genes have been building up to the biggest cell defense signaling network, composed of not only 22+ FA proteins but also ATM, ATR, and many other non-FA proteins. The FA D2 group protein (FANCD2) and its paralog form the focal point of FA signaling to converge the effects of its upstream players in response to a variety of cellular insults and simultaneously with downstream players to protect humans from contracting diseases, including aging and cancer. In this review, we update and discuss how the FA signaling crucially eases cellular stresses through understanding its focal point. Full article
(This article belongs to the Special Issue DNA Damage Response, an Update)
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26 pages, 2570 KiB  
Review
DNA Repair in Haploid Context
by Loïs Mourrain and Guylain Boissonneault
Int. J. Mol. Sci. 2021, 22(22), 12418; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212418 - 17 Nov 2021
Cited by 6 | Viewed by 2266
Abstract
DNA repair is a well-covered topic as alteration of genetic integrity underlies many pathological conditions and important transgenerational consequences. Surprisingly, the ploidy status is rarely considered although the presence of homologous chromosomes dramatically impacts the repair capacities of cells. This is especially important [...] Read more.
DNA repair is a well-covered topic as alteration of genetic integrity underlies many pathological conditions and important transgenerational consequences. Surprisingly, the ploidy status is rarely considered although the presence of homologous chromosomes dramatically impacts the repair capacities of cells. This is especially important for the haploid gametes as they must transfer genetic information to the offspring. An understanding of the different mechanisms monitoring genetic integrity in this context is, therefore, essential as differences in repair pathways exist that differentiate the gamete’s role in transgenerational inheritance. Hence, the oocyte must have the most reliable repair capacity while sperm, produced in large numbers and from many differentiation steps, are expected to carry de novo variations. This review describes the main DNA repair pathways with a special emphasis on ploidy. Differences between Saccharomyces cerevisiae and Schizosaccharomyces pombe are especially useful to this aim as they can maintain a diploid and haploid life cycle respectively. Full article
(This article belongs to the Special Issue DNA Damage Response, an Update)
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34 pages, 30446 KiB  
Review
Mutagenic Consequences of Sublethal Cell Death Signaling
by Christine J. Hawkins and Mark A. Miles
Int. J. Mol. Sci. 2021, 22(11), 6144; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22116144 - 07 Jun 2021
Cited by 7 | Viewed by 3630
Abstract
Many human cancers exhibit defects in key DNA damage response elements that can render tumors insensitive to the cell death-promoting properties of DNA-damaging therapies. Using agents that directly induce apoptosis by targeting apoptotic components, rather than relying on DNA damage to indirectly stimulate [...] Read more.
Many human cancers exhibit defects in key DNA damage response elements that can render tumors insensitive to the cell death-promoting properties of DNA-damaging therapies. Using agents that directly induce apoptosis by targeting apoptotic components, rather than relying on DNA damage to indirectly stimulate apoptosis of cancer cells, may overcome classical blocks exploited by cancer cells to evade apoptotic cell death. However, there is increasing evidence that cells surviving sublethal exposure to classical apoptotic signaling may recover with newly acquired genomic changes which may have oncogenic potential, and so could theoretically spur the development of subsequent cancers in cured patients. Encouragingly, cells surviving sublethal necroptotic signaling did not acquire mutations, suggesting that necroptosis-inducing anti-cancer drugs may be less likely to trigger therapy-related cancers. We are yet to develop effective direct inducers of other cell death pathways, and as such, data regarding the consequences of cells surviving sublethal stimulation of those pathways are still emerging. This review details the currently known mutagenic consequences of cells surviving different cell death signaling pathways, with implications for potential oncogenic transformation. Understanding the mechanisms of mutagenesis associated (or not) with various cell death pathways will guide us in the development of future therapeutics to minimize therapy-related side effects associated with DNA damage. Full article
(This article belongs to the Special Issue DNA Damage Response, an Update)
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