scholarly journals RAD52 Functions in Homologous Recombination and Its Importance on Genomic Integrity Maintenance and Cancer Therapy

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1622 ◽  
Author(s):  
Augusto Nogueira ◽  
Mara Fernandes ◽  
Raquel Catarino ◽  
Rui Medeiros
Keyword(s):  
Dna Damage ◽  
Cancer Therapy ◽  
Homologous Recombination ◽  
Signaling Pathways ◽  
Chromosomal Abnormalities ◽  
Cell Cycle Checkpoints ◽  
Cytotoxic Agents ◽  
Dna Damage Signaling ◽  
Physiological Processes ◽  
Repair Mechanisms

Genomes are continually subjected to DNA damage whether they are induced from intrinsic physiological processes or extrinsic agents. Double-stranded breaks (DSBs) are the most injurious type of DNA damage, being induced by ionizing radiation (IR) and cytotoxic agents used in cancer treatment. The failure to repair DSBs can result in aberrant chromosomal abnormalities which lead to cancer development. An intricate network of DNA damage signaling pathways is usually activated to eliminate these damages and to restore genomic stability. These signaling pathways include the activation of cell cycle checkpoints, DNA repair mechanisms, and apoptosis induction, also known as DNA damage response (DDR)-mechanisms. Remarkably, the homologous recombination (HR) is the major DSBs repairing pathway, in which RAD52 gene has a crucial repairing role by promoting the annealing of complementary single-stranded DNA and by stimulating RAD51 recombinase activity. Evidence suggests that variations in RAD52 expression can influence HR activity and, subsequently, influence the predisposition and treatment efficacy of cancer. In this review, we present several reports in which the down or upregulation of RAD52 seems to be associated with different carcinogenic processes. In addition, we discuss RAD52 inhibition in DDR-defective cancers as a possible target to improve cancer therapy efficacy.

scholarly journals Platinum Complexes in Colorectal Cancer and Other Solid Tumors

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2073
Author(s):  
Beate Köberle ◽  
Sarah Schoch
Keyword(s):  
Colorectal Cancer ◽  
Dna Damage ◽  
Dna Repair ◽  
Cancer Cells ◽  
Cisplatin Resistance ◽  
Platinum Complexes ◽  
Dna Lesions ◽  
Dna Damage Signaling ◽  
Repair Mechanisms ◽  
P53 Inactivation

Cisplatin is one of the most commonly used drugs for the treatment of various solid neoplasms, including testicular, lung, ovarian, head and neck, and bladder cancers. Unfortunately, the therapeutic efficacy of cisplatin against colorectal cancer is poor. Various mechanisms appear to contribute to cisplatin resistance in cancer cells, including reduced drug accumulation, enhanced drug detoxification, modulation of DNA repair mechanisms, and finally alterations in cisplatin DNA damage signaling preventing apoptosis in cancer cells. Regarding colorectal cancer, defects in mismatch repair and altered p53-mediated DNA damage signaling are the main factors controlling the resistance phenotype. In particular, p53 inactivation appears to be associated with chemoresistance and poor prognosis. To overcome resistance in cancers, several strategies can be envisaged. Improved cisplatin analogues, which retain activity in resistant cancer, might be applied. Targeting p53-mediated DNA damage signaling provides another therapeutic strategy to circumvent cisplatin resistance. This review provides an overview on the DNA repair pathways involved in the processing of cisplatin damage and will describe signal transduction from cisplatin DNA lesions, with special attention given to colorectal cancer cells. Furthermore, examples for improved platinum compounds and biochemical modulators of cisplatin DNA damage signaling will be presented in the context of colon cancer therapy.

scholarly journals A Role for E1B-AP5 in ATR Signaling Pathways during Adenovirus Infection

2008 ◽  
Vol 82 (15) ◽  
pp. 7640-7652 ◽  
Author(s):  
Andrew N. Blackford ◽  
Rachel K. Bruton ◽  
Orkide Dirlik ◽  
Grant S. Stewart ◽  
A. Malcolm R. Taylor ◽  
...  
Keyword(s):  
Dna Damage ◽  
Viral Replication ◽  
Signaling Pathways ◽  
Protein A ◽  
Interacting Protein ◽  
Dna Damage Signaling ◽  
Infected Cells ◽  
Cellular Dna ◽  
Nuclear Ribonucleoprotein

ABSTRACT E1B-55K-associated protein 5 (E1B-AP5) is a cellular, heterogeneous nuclear ribonucleoprotein that is targeted by adenovirus (Ad) E1B-55K during infection. The function of E1B-AP5 during infection, however, remains largely unknown. Given the role of E1B-55K targets in the DNA damage response, we examined whether E1B-AP5 function was integral to these pathways. Here, we show a novel role for E1B-AP5 as a key regulator of ATR signaling pathways activated during Ad infection. E1B-AP5 is recruited to viral replication centers during infection, where it colocalizes with ATR-interacting protein (ATRIP) and the ATR substrate replication protein A 32 (RPA32). Indeed, E1B-AP5 associates with ATRIP and RPA complex component RPA70 in both uninfected and Ad-infected cells. Additionally, glutathione S-transferase pull-downs show that E1B-AP5 associates with RPA components RPA70 and RPA32 directly in vitro. E1B-AP5 is required for the ATR-dependent phosphorylation of RPA32 during infection and contributes to the Ad-induced phosphorylation of Smc1 and H2AX. In this regard, it is interesting that Ad5 and Ad12 differentially promote the phosphorylation of RPA32, Rad9, and Smc1 during infection such that Ad12 promotes a significant phosphorylation of RPA32 and Rad9, whereas Ad5 only weakly promotes RPA32 phosphorylation and does not induce Rad9 phosphorylation. These data suggest that Ad5 and Ad12 have evolved different strategies to regulate DNA damage signaling pathways during infection in order to promote viral replication. Taken together, our results define a role for E1B-AP5 in ATR signaling pathways activated during infection. This might have broader implications for the regulation of ATR activity during cellular DNA replication or in response to DNA damage.

scholarly journals DNA repair system defects - role in oncogenesis and cancer therapy

2014 ◽  
Vol 95 (3) ◽  
pp. 307-314
Author(s):  
S V Boychuk ◽  
B R Ramazanov
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Cancer Therapy ◽  
Single Case ◽  
Published Data ◽  
Repair System ◽  
Damage Repair ◽  
Anti Cancer ◽  
Repair Mechanisms ◽  
Acquired Abnormalities

Inherited and acquired abnormalities in DNA damage repair system may lead to cancer and other diseases, as well as to act as one of the key factors determining the patient’s responsiveness to chemo- and radiotherapy. Nowadays, the principles of the personalized therapy, based on specific features of disease development and pathogenesis of a solitary organism or in a small group, are applied to treat a broad number of diseases, including cancers. This approach allows to choose the most effective cancer therapy in every single case of cancer, based on the genetic analysis and expression level of specific proteins. One of the promising approaches for increasing the effectiveness of non-surgical cancer treatments - to develop the methods to increase the cancer cells sensitivity to conducted chemotherapy, based on using the DNA repair system defects for the better anti-cancer effect. The review covers some types of DNA repair system defects occurring while chemo- and radiotherapy. Perspectives of the possible influences on DNA repair mechanisms treated as possible targets for both anti-cancer treatment and for increasing the effects of cancer chemo- and radiotherapy, are discussed in the review considering the available published data and results of own research. DNA repair system defects play an important role in cancer genesis, but as well can determine the good response of patients with such defects to chemo- and radiotherapy (inducing different types of DNA damage).

scholarly journals Inactivation of mouse Hus1 results in genomic instability and impaired responses to genotoxic stress

2000 ◽  
Vol 14 (15) ◽  
pp. 1886-1898 ◽  
Author(s):  
Robert S. Weiss ◽  
Tamar Enoch ◽  
Philip Leder
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Replication ◽  
Chromosomal Abnormalities ◽  
Genotoxic Stress ◽  
Eukaryotic Cell ◽  
Cell Cycle Checkpoint ◽  
Cell Cycle Checkpoints ◽  
Genome Damage

The eukaryotic cell cycle is overseen by regulatory mechanisms, termed checkpoints, that respond to DNA damage, mitotic spindle defects, and errors in the ordering of cell cycle events. The DNA replication and DNA damage cell cycle checkpoints of the fission yeastSchizosaccharomyces pombe require the hus1+(hydroxyurea sensitive) gene. To determine the role of the mouse homolog of hus1+ in murine development and cell cycle checkpoint function, we produced a targeted disruption of mouse Hus1. Inactivation of Hus1results in mid-gestational embryonic lethality due to widespread apoptosis and defective development of essential extra-embryonic tissues. DNA damage-inducible genes are up-regulated inHus1-deficient embryos, and primary cells fromHus1-null embryos contain increased spontaneous chromosomal abnormalities, suggesting that loss of Hus1 leads to an accumulation of genome damage. Embryonic fibroblasts lackingHus1 fail to proliferate in vitro, but inactivation ofp21 allows for the continued growth of Hus1-deficient cells.Hus1−/−p21−/−cells display a unique profile of significantly heightened sensitivity to hydroxyurea, a DNA replication inhibitor, and ultraviolet light, but only slightly increased sensitivity to ionizing radiation. Taken together, these results indicate that mouse Hus1 functions in the maintenance of genomic stability and additionally identify an evolutionarily-conserved role for Hus1 in mediating cellular responses to genotoxins.

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