scholarly journals The Emerging Role of Cohesin in the DNA Damage Response

Genes ◽  
2018 ◽  
Vol 9 (12) ◽  
pp. 581 ◽  
Author(s):  
Ireneusz Litwin ◽  
Ewa Pilarczyk ◽  
Robert Wysocki
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Developmental Disorders ◽  
Molecular Mechanisms ◽  
Genetic Material ◽  
Dna Damage Signaling ◽  
Sister Chromatids ◽  
Chromatid Cohesion ◽  
Damage Response

Faithful transmission of genetic material is crucial for all organisms since changes in genetic information may result in genomic instability that causes developmental disorders and cancers. Thus, understanding the mechanisms that preserve genome integrity is of fundamental importance. Cohesin is a multiprotein complex whose canonical function is to hold sister chromatids together from S-phase until the onset of anaphase to ensure the equal division of chromosomes. However, recent research points to a crucial function of cohesin in the DNA damage response (DDR). In this review, we summarize recent advances in the understanding of cohesin function in DNA damage signaling and repair. First, we focus on cohesin architecture and molecular mechanisms that govern sister chromatid cohesion. Next, we briefly characterize the main DDR pathways. Finally, we describe mechanisms that determine cohesin accumulation at DNA damage sites and discuss possible roles of cohesin in DDR.

scholarly journals The nucleosome: orchestrating DNA damage signaling and repair within chromatin

2016 ◽  
Vol 94 (5) ◽  
pp. 381-395 ◽  
Author(s):  
Poonam Agarwal ◽  
Kyle M. Miller
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Histone Modifications ◽  
Chromatin Structure ◽  
Molecular Mechanisms ◽  
Current View ◽  
Target Specificity ◽  
Dna Damage Signaling ◽  
Damage Response ◽  
Transcription And Replication

DNA damage occurs within the chromatin environment, which ultimately participates in regulating DNA damage response (DDR) pathways and repair of the lesion. DNA damage activates a cascade of signaling events that extensively modulates chromatin structure and organization to coordinate DDR factor recruitment to the break and repair, whilst also promoting the maintenance of normal chromatin functions within the damaged region. For example, DDR pathways must avoid conflicts between other DNA-based processes that function within the context of chromatin, including transcription and replication. The molecular mechanisms governing the recognition, target specificity, and recruitment of DDR factors and enzymes to the fundamental repeating unit of chromatin, i.e., the nucleosome, are poorly understood. Here we present our current view of how chromatin recognition by DDR factors is achieved at the level of the nucleosome. Emerging evidence suggests that the nucleosome surface, including the nucleosome acidic patch, promotes the binding and activity of several DNA damage factors on chromatin. Thus, in addition to interactions with damaged DNA and histone modifications, nucleosome recognition by DDR factors plays a key role in orchestrating the requisite chromatin response to maintain both genome and epigenome integrity.

scholarly journals The Role of E3, E4 Ubiquitin Ligase (UBE4B) in Human Pathologies

Cancers ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 62 ◽  
Author(s):  
Nikolaos Antoniou ◽  
Nefeli Lagopati ◽  
Dimitrios Ilias Balourdas ◽  
Michail Nikolaou ◽  
Alexandros Papalampros ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Ubiquitin Ligase ◽  
Molecular Mechanisms ◽  
Ubiquitin Ligases ◽  
Cellular Functions ◽  
P53 Expression ◽  
Damage Response ◽  
Mechanisms Of Carcinogenesis

The genome is exposed daily to many deleterious factors. Ubiquitination is a mechanism that regulates several crucial cellular functions, allowing cells to react upon various stimuli in order to preserve their homeostasis. Ubiquitin ligases act as specific regulators and actively participate among others in the DNA damage response (DDR) network. UBE4B is a newly identified member of E3 ubiquitin ligases that appears to be overexpressed in several human neoplasms. The aim of this review is to provide insights into the role of UBE4B ubiquitin ligase in DDR and its association with p53 expression, shedding light particularly on the molecular mechanisms of carcinogenesis.

scholarly journals DNA Damage Response in Multiple Myeloma: The Role of the Tumor Microenvironment

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 504
Author(s):  
Takayuki Saitoh ◽  
Tsukasa Oda
Keyword(s):  
Multiple Myeloma ◽  
Dna Damage ◽  
Dna Repair ◽  
Tumor Microenvironment ◽  
Dna Damage Response ◽  
Genetic Instability ◽  
Dna Repair Mechanisms ◽  
Damage Response ◽  
Repair Mechanisms

Multiple myeloma (MM) is an incurable plasma cell malignancy characterized by genomic instability. MM cells present various forms of genetic instability, including chromosomal instability, microsatellite instability, and base-pair alterations, as well as changes in chromosome number. The tumor microenvironment and an abnormal DNA repair function affect genetic instability in this disease. In addition, states of the tumor microenvironment itself, such as inflammation and hypoxia, influence the DNA damage response, which includes DNA repair mechanisms, cell cycle checkpoints, and apoptotic pathways. Unrepaired DNA damage in tumor cells has been shown to exacerbate genomic instability and aberrant features that enable MM progression and drug resistance. This review provides an overview of the DNA repair pathways, with a special focus on their function in MM, and discusses the role of the tumor microenvironment in governing DNA repair mechanisms.

Dissecting the Role of Thyrotropin in the DNA Damage Response in Human Thyrocytes after 131I, γ Radiation and H2O2

2019 ◽  
Vol 105 (3) ◽  
pp. 839-853
Author(s):  
Aglaia Kyrilli ◽  
David Gacquer ◽  
Vincent Detours ◽  
Anne Lefort ◽  
Frédéric Libert ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Iodide Uptake ◽  
Transcriptomic Response ◽  
Uptake Inhibition ◽  
Γ Radiation ◽  
Damage Response

Abstract Background The early molecular events in human thyrocytes after 131I exposure have not yet been unravelled. Therefore, we investigated the role of TSH in the 131I-induced DNA damage response and gene expression in primary cultured human thyrocytes. Methods Following exposure of thyrocytes, in the presence or absence of TSH, to 131I (β radiation), γ radiation (3 Gy), and hydrogen peroxide (H2O2), we assessed DNA damage, proliferation, and cell-cycle status. We conducted RNA sequencing to profile gene expression after each type of exposure and evaluated the influence of TSH on each transcriptomic response. Results Overall, the thyrocyte responses following exposure to β or γ radiation and to H2O2 were similar. However, TSH increased 131I-induced DNA damage, an effect partially diminished after iodide uptake inhibition. Specifically, TSH increased the number of DNA double-strand breaks in nonexposed thyrocytes and thus predisposed them to greater damage following 131I exposure. This effect most likely occurred via Gα q cascade and a rise in intracellular reactive oxygen species (ROS) levels. β and γ radiation prolonged thyroid cell-cycle arrest to a similar extent without sign of apoptosis. The gene expression profiles of thyrocytes exposed to β/γ radiation or H2O2 were overlapping. Modulations in genes involved in inflammatory response, apoptosis, and proliferation were observed. TSH increased the number and intensity of modulation of differentially expressed genes after 131I exposure. Conclusions TSH specifically increased 131I-induced DNA damage probably via a rise in ROS levels and produced a more prominent transcriptomic response after exposure to 131I.

Role of H2AX in DNA damage response and human cancers

2009 ◽  
Vol 681 (2-3) ◽  
pp. 180-188 ◽  
Author(s):  
Niloo Srivastava ◽  
Sailesh Gochhait ◽  
Peter de Boer ◽  
Rameshwar N.K. Bamezai
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Human Cancers ◽  
Damage Response

scholarly journals A novel role of the chromokinesin Kif4A in DNA damage response

Cell Cycle ◽  
2008 ◽  
Vol 7 (13) ◽  
pp. 2013-2020 ◽  
Author(s):  
Guikai Wu ◽  
Longen Zhou ◽  
Lily Khidr ◽  
Xuning Emily Guo ◽  
Wankee Kim ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Damage Response

scholarly journals Nucleotide Excision Repair Protein Rad23 Regulates Cell Virulence Independent of Rad4 in Candida albicans

mSphere ◽  
2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Jia Feng ◽  
Shuangyan Yao ◽  
Yansong Dong ◽  
Jing Hu ◽  
Malcolm Whiteway ◽  
...  
Keyword(s):  
Dna Damage ◽  
Candida Albicans ◽  
Nucleotide Excision Repair ◽  
Dna Damage Response ◽  
Excision Repair ◽  
Content Type ◽  
Virulence Regulation ◽  
Nucleotide Excision ◽  
Damage Response

ABSTRACT In the pathogenic yeast Candida albicans, the DNA damage response contributes to pathogenicity by regulating cell morphology transitions and maintaining survival in response to DNA damage induced by reactive oxygen species (ROS) in host cells. However, the function of nucleotide excision repair (NER) in C. albicans has not been extensively investigated. To better understand the DNA damage response and its role in virulence, we studied the function of the Rad23 nucleotide excision repair protein in detail. The RAD23 deletion strain and overexpression strain both exhibit UV sensitivity, confirming the critical role of RAD23 in the nucleotide excision repair pathway. Genetic interaction assays revealed that the role of RAD23 in the UV response relies on RAD4 but is independent of RAD53, MMS22, and RAD18. RAD4 and RAD23 have similar roles in regulating cell morphogenesis and biofilm formation; however, only RAD23, but not RAD4, plays a negative role in virulence regulation in a mouse model. We found that the RAD23 deletion strain showed decreased survival in a Candida-macrophage interaction assay. Transcriptome sequencing (RNA-seq) and quantitative real-time PCR (qRT-PCR) data further revealed that RAD23, but not RAD4, regulates the transcription of a virulence factor, SUN41, suggesting a unique role of RAD23 in virulence regulation. Taking these observations together, our work reveals that the RAD23-related nucleotide excision pathway plays a critical role in the UV response but may not play a direct role in virulence. The virulence-related role of RAD23 may rely on the regulation of several virulence factors, which may give us further understanding about the linkage between DNA damage repair and virulence regulation in C. albicans. IMPORTANCE Candida albicans remains a significant threat to the lives of immunocompromised people. An understanding of the virulence and infection ability of C. albicans cells in the mammalian host may help with clinical treatment and drug discovery. The DNA damage response pathway is closely related to morphology regulation and virulence, as well as the ability to survive in host cells. In this study, we checked the role of the nucleotide excision repair (NER) pathway, the key repair system that functions to remove a large variety of DNA lesions such as those caused by UV light, but whose function has not been well studied in C. albicans. We found that Rad23, but not Rad4, plays a role in virulence that appears independent of the function of the NER pathway. Our research revealed that the NER pathway represented by Rad4/Rad23 may not play a direct role in virulence but that Rad23 may play a unique role in regulating the transcription of virulence genes that may contribute to the virulence of C. albicans.

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