scholarly journals The role of ATXR6 expression in modulating genome stability and transposable element repression in Arabidopsis

2022 ◽  
Vol 119 (3) ◽  
pp. e2115570119
Author(s):  
Magdalena E. Potok ◽  
Zhenhui Zhong ◽  
Colette L. Picard ◽  
Qikun Liu ◽  
Truman Do ◽  
...  
Keyword(s):  
Dna Damage ◽  
Genome Stability ◽  
Null Allele ◽  
Epigenetic Changes ◽  
Germline Development ◽  
Tissue Specific ◽  
Damage Response ◽  
Female Germline

ARABIDOPSIS TRITHORAX-RELATED PROTEIN 5 (ATXR5) AND ATXR6 are required for the deposition of H3K27me1 and for maintaining genomic stability in Arabidopsis. Reduction of ATXR5/6 activity results in activation of DNA damage response genes, along with tissue-specific derepression of transposable elements (TEs), chromocenter decompaction, and genomic instability characterized by accumulation of excess DNA from heterochromatin. How loss of ATXR5/6 and H3K27me1 leads to these phenotypes remains unclear. Here we provide extensive characterization of the atxr5/6 hypomorphic mutant by comprehensively examining gene expression and epigenetic changes in the mutant. We found that the tissue-specific phenotypes of TE derepression and excessive DNA in this atxr5/6 mutant correlated with residual ATXR6 expression from the hypomorphic ATXR6 allele. However, up-regulation of DNA damage genes occurred regardless of ATXR6 levels and thus appears to be a separable process. We also isolated an atxr6-null allele which showed that ATXR5 and ATXR6 are required for female germline development. Finally, we characterize three previously reported suppressors of the hypomorphic atxr5/6 mutant and show that these rescue atxr5/6 via distinct mechanisms, two of which involve increasing H3K27me1 levels.

scholarly journals Characterization of SMG7 14-3-3-like domain reveals phosphoserine binding-independent regulation of p53 and UPF1

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Lauren E. Cowen ◽  
Hongwei Luo ◽  
Yi Tang
Keyword(s):  
Dna Damage ◽  
Protein Interactions ◽  
Cell Growth Arrest ◽  
Damage Response ◽  
Nonsense Mediated Mrna Decay ◽  
Dependent Cell ◽  
Dependent Protein ◽  
Client Proteins

Abstract The 14-3-3-related protein SMG7 plays critical roles in regulation of DNA damage response and nonsense-mediated mRNA decay (NMD). Like 14-3-3, SMG7 engages phosphoserine-dependent protein interactions; however, the precise role of phosphorylation-mediated SMG7 binding remains unknown. Here, we show that DNA damage-induced SMG7-p53 binding requires phosphorylated Ser15 on p53, and that substitution of the conserved lysine residue K66 in the SMG7 14-3-3-like domain with the glutamic acid (E) abolishes interactions with its client proteins p53 and UPF1. Unexpectedly, loss of phosphoserine-dependent SMG7 binding does not significantly affect p53 stabilization/activation, and p53-dependent cell growth arrest or apoptosis upon DNA damage. Also surprisingly, cells expressing the SMG7 K66E-knockin mutant retain fully functional UPF1-mediated NMD. These findings are highly unusual, given that phosphorylation-mediated 14-3-3 binding has essential roles in numerous cellular signaling pathways. Thus, our studies suggest that 14-3-3-like proteins such as SMG7 likely function using additional distinct regulatory mechanisms besides phosphoserine-mediated protein interactions.

scholarly journals Multifunctional Role of ATM/Tel1 Kinase in Genome Stability: From the DNA Damage Response to Telomere Maintenance

2014 ◽  
Vol 2014 ◽  
pp. 1-17 ◽  
Author(s):  
Enea Gino Di Domenico ◽  
Elena Romano ◽  
Paola Del Porto ◽  
Fiorentina Ascenzioni
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Ataxia Telangiectasia ◽  
Genome Stability ◽  
Genetic Disorder ◽  
Cell Cycle Control ◽  
Premature Aging ◽  
Telomere Maintenance ◽  
Damage Response

The mammalian protein kinase ataxia telangiectasia mutated (ATM) is a key regulator of the DNA double-strand-break response and belongs to the evolutionary conserved phosphatidylinositol-3-kinase-related protein kinases. ATM deficiency causes ataxia telangiectasia (AT), a genetic disorder that is characterized by premature aging, cerebellar neuropathy, immunodeficiency, and predisposition to cancer. AT cells show defects in the DNA damage-response pathway, cell-cycle control, and telomere maintenance and length regulation. Likewise, inSaccharomyces cerevisiae, haploid strains defective in theTEL1gene, the ATM ortholog, show chromosomal aberrations and short telomeres. In this review, we outline the complex role of ATM/Tel1 in maintaining genomic stability through its control of numerous aspects of cellular survival. In particular, we describe how ATM/Tel1 participates in the signal transduction pathways elicited by DNA damage and in telomere homeostasis and its importance as a barrier to cancer development.

scholarly journals SIRT7: a sentinel of genome stability

Open Biology ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 210047
Author(s):  
Ming Tang ◽  
Huangqi Tang ◽  
Bo Tu ◽  
Wei-Guo Zhu
Keyword(s):  
Dna Damage ◽  
Genome Stability ◽  
Biological Function ◽  
Critical Role ◽  
Class Iii ◽  
Cellular Processes ◽  
The Past ◽  
Damage Response ◽  
Normal Gene

SIRT7 is a class III histone deacetylase that belongs to the sirtuin family. The past two decades have seen numerous breakthroughs in terms of understanding SIRT7 biological function. We now know that this enzyme is involved in diverse cellular processes, ranging from gene regulation to genome stability, ageing and tumorigenesis. Genomic instability is one hallmark of cancer and ageing; it occurs as a result of excessive DNA damage. To counteract such instability, cells have evolved a sophisticated regulated DNA damage response mechanism that restores normal gene function. SIRT7 seems to have a critical role in this response, and it is recruited to sites of DNA damage where it recruits downstream repair factors and directs chromatin regulation. In this review, we provide an overview of the role of SIRT7 in DNA repair and maintaining genome stability. We pay particular attention to the implications of SIRT7 function in cancer and ageing.

scholarly journals Role of Deubiquitinating Enzymes in DNA Repair

2015 ◽  
Vol 36 (4) ◽  
pp. 524-544 ◽  
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.

Succinylation at a key residue of FEN1 is involved in the DNA damage response to maintain genome stability

2020 ◽  
Vol 319 (4) ◽  
pp. C657-C666
Author(s):  
Rongyi Shi ◽  
Yiyi Wang ◽  
Ya Gao ◽  
Xiaoli Xu ◽  
Shuyu Mao ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Replication Fork ◽  
Genome Stability ◽  
Damage Response ◽  
Dna Replication And Repair ◽  
Fork Stalling ◽  
Stalled Replication Forks ◽  
Maintain Genome Stability

Human flap endonuclease 1 (FEN1) is a structure-specific, multifunctional endonuclease essential for DNA replication and repair. Our previous study showed that in response to DNA damage, FEN1 interacts with the PCNA-like Rad9-Rad1-Hus1 complex instead of PCNA to engage in DNA repair activities, such as stalled DNA replication fork repair, and undergoes SUMOylation by SUMO-1. Here, we report that succinylation of FEN1 was stimulated in response to DNA replication fork-stalling agents, such as ultraviolet (UV) irradiation, hydroxyurea, camptothecin, and mitomycin C. K200 is a key succinylation site of FEN1 that is essential for gap endonuclease activity and could be suppressed by methylation and stimulated by phosphorylation to promote SUMO-1 modification. Succinylation at K200 of FEN1 promoted the interaction of FEN1 with the Rad9-Rad1-Hus1 complex to rescue stalled replication forks. Impairment of FEN1 succinylation led to the accumulation of DNA damage and heightened sensitivity to fork-stalling agents. Altogether, our findings suggest an important role of FEN1 succinylation in regulating its roles in DNA replication and repair, thus maintaining genome stability.

Maintenance of genome stability: the unifying role of interconnections between the DNA damage response and RNA-processing pathways

2018 ◽  
Vol 64 (5) ◽  
pp. 971-983 ◽  
Author(s):  
B. Mikolaskova ◽  
M. Jurcik ◽  
I. Cipakova ◽  
M. Kretova ◽  
M. Chovanec ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Rna Processing ◽  
Genome Stability ◽  
Damage Response ◽  
Processing Pathways

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.

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