scholarly journals Emerging roles of RNA modifications in genome integrity

2020 ◽  
Author(s):  
Seo Yun Lee ◽  
Jae Jin Kim ◽  
Kyle M Miller
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Dna Repair ◽  
Genome Stability ◽  
Strand Break ◽  
Human Diseases ◽  
Genome Integrity ◽  
Rna Modification ◽  
Rna Modifications ◽  
Dna Double Strand Break

Abstract Post-translational modifications of proteins are well-established participants in DNA damage response (DDR) pathways, which function in the maintenance of genome integrity. Emerging evidence is starting to reveal the involvement of modifications on RNA in the DDR. RNA modifications are known regulators of gene expression but how and if they participate in DNA repair and genome maintenance has been poorly understood. Here, we review several studies that have now established RNA modifications as key components of DNA damage responses. RNA modifying enzymes and the binding proteins that recognize these modifications localize to and participate in the repair of UV-induced and DNA double-strand break lesions. RNA modifications have a profound effect on DNA–RNA hybrids (R-loops) at DNA damage sites, a structure known to be involved in DNA repair and genome stability. Given the importance of the DDR in suppressing mutations and human diseases such as neurodegeneration, immunodeficiencies, cancer and aging, RNA modification pathways may be involved in human diseases not solely through their roles in gene expression but also by their ability to impact DNA repair and genome stability.

Perfecting DNA double-strand break repair on transcribed chromatin

2020 ◽  
Vol 64 (5) ◽  
pp. 705-719 ◽  
Author(s):  
Xin Yi Tan ◽  
Michael S.Y. Huen
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Chromosomal Aberrations ◽  
Chromatin Structure ◽  
Genome Stability ◽  
Transcriptional Control ◽  
Strand Break ◽  
Double Strand Break ◽  
Dna Double Strand Break ◽  
Molecular Bases

Abstract Timely repair of DNA double-strand break (DSB) entails coordination with the local higher order chromatin structure and its transaction activities, including transcription. Recent studies are uncovering how DSBs trigger transient suppression of nearby transcription to permit faithful DNA repair, failing of which leads to elevated chromosomal aberrations and cell hypersensitivity to DNA damage. Here, we summarize the molecular bases for transcriptional control during DSB metabolism, and discuss how the exquisite coordination between the two DNA-templated processes may underlie maintenance of genome stability and cell homeostasis.

scholarly journals Preserving genome integrity in human cells via DNA double-strand break repair

2020 ◽  
Vol 31 (9) ◽  
pp. 859-865 ◽  
Author(s):  
Ryan B. Jensen ◽  
Eli Rothenberg
Keyword(s):  
Dna Repair ◽  
Strand Break ◽  
Double Strand Break ◽  
Human Cells ◽  
Cell Cycle Checkpoints ◽  
Human Diseases ◽  
Genome Integrity ◽  
Dsb Repair ◽  
Dna Double Strand Break ◽  
Repair Pathways

The efficient maintenance of genome integrity in the face of cellular stress is vital to protect against human diseases such as cancer. DNA replication, chromatin dynamics, cellular signaling, nuclear architecture, cell cycle checkpoints, and other cellular activities contribute to the delicate spatiotemporal control that cells utilize to regulate and maintain genome stability. This perspective will highlight DNA double-strand break (DSB) repair pathways in human cells, how DNA repair failures can lead to human disease, and how PARP inhibitors have emerged as a novel clinical therapy to treat homologous recombination-deficient tumors. We briefly discuss how failures in DNA repair produce a permissive genetic environment in which preneoplastic cells evolve to reach their full tumorigenic potential. Finally, we conclude that an in-depth understanding of DNA DSB repair pathways in human cells will lead to novel therapeutic strategies to treat cancer and potentially other human diseases.

scholarly journals A SWI/SNF subunit regulates chromosomal dissociation of structural maintenance complex 5 during DNA repair in plant cells

2019 ◽  
Vol 116 (30) ◽  
pp. 15288-15296 ◽  
Author(s):  
Jieming Jiang ◽  
Ning Mao ◽  
Huan Hu ◽  
Jiahang Tang ◽  
Danlu Han ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Genome Stability ◽  
Damage Accumulation ◽  
Protein Complexes ◽  
Plant Cells ◽  
Strand Break ◽  
Interacting Protein ◽  
Dna Double Strand Break ◽  
A Subunit

DNA damage decreases genome stability and alters genetic information in all organisms. Conserved protein complexes have been evolved for DNA repair in eukaryotes, such as the structural maintenance complex 5/6 (SMC5/6), a chromosomal ATPase involved in DNA double-strand break (DSB) repair. Several factors have been identified for recruitment of SMC5/6 to DSBs, but this complex is also associated with chromosomes under normal conditions; how SMC5/6 dissociates from its original location and moves to DSB sites is completely unknown. In this study, we determined that SWI3B, a subunit of the SWI/SNF complex, is an SMC5-interacting protein in Arabidopsis thialiana. Knockdown of SWI3B or SMC5 results in increased DNA damage accumulation. During DNA damage, SWI3B expression is induced, but the SWI3B protein is not localized at DSBs. Notably, either knockdown or overexpression of SWI3B disrupts the DSB recruitment of SMC5 in response to DNA damage. Overexpression of a cotranscriptional activator ADA2b rescues the DSB localization of SMC5 dramatically in the SWI3B-overexpressing cells but only weakly in the SWI3B knockdown cells. Biochemical data confirmed that ADA2b attenuates the interaction between SWI3B and SMC5 and that SWI3B promotes the dissociation of SMC5 from chromosomes. In addition, overexpression of SMC5 reduces DNA damage accumulation in the SWI3B knockdown plants. Collectively, these results indicate that the presence of an appropriate level of SWI3B enhances dissociation of SMC5 from chromosomes for its further recruitment at DSBs during DNA damage in plant cells.

scholarly journals Genome Maintenance Mechanisms at the Chromatin Level

2021 ◽  
Vol 22 (19) ◽  
pp. 10384
Author(s):  
Hirotomo Takatsuka ◽  
Atsushi Shibata ◽  
Masaaki Umeda
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Genome Stability ◽  
Genotoxic Stress ◽  
Genome Integrity ◽  
Easy Access ◽  
Order Structure ◽  
Chromatin Modifications ◽  
Level Control ◽  
Regulatory Systems

Genome integrity is constantly threatened by internal and external stressors, in both animals and plants. As plants are sessile, a variety of environment stressors can damage their DNA. In the nucleus, DNA twines around histone proteins to form the higher-order structure “chromatin”. Unraveling how chromatin transforms on sensing genotoxic stress is, thus, key to understanding plant strategies to cope with fluctuating environments. In recent years, accumulating evidence in plant research has suggested that chromatin plays a crucial role in protecting DNA from genotoxic stress in three ways: (1) changes in chromatin modifications around damaged sites enhance DNA repair by providing a scaffold and/or easy access to DNA repair machinery; (2) DNA damage triggers genome-wide alterations in chromatin modifications, globally modulating gene expression required for DNA damage response, such as stem cell death, cell-cycle arrest, and an early onset of endoreplication; and (3) condensed chromatin functions as a physical barrier against genotoxic stressors to protect DNA. In this review, we highlight the chromatin-level control of genome stability and compare the regulatory systems in plants and animals to find out unique mechanisms maintaining genome integrity under genotoxic stress.

scholarly journals Akt/PKB suppresses DNA damage processing and checkpoint activation in late G2

2010 ◽  
Vol 190 (3) ◽  
pp. 297-305 ◽  
Author(s):  
Naihan Xu ◽  
Nadia Hegarat ◽  
Elizabeth J. Black ◽  
Mary T. Scott ◽  
Helfrid Hochegger ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Protein A ◽  
Strand Break ◽  
Checkpoint Activation ◽  
Interacting Protein ◽  
Dna Double Strand Break ◽  
Radiation Induced ◽  
G2 Cells ◽  
Tumor Types

Using chemical genetics to reversibly inhibit Cdk1, we find that cells arrested in late G2 are unable to delay mitotic entry after irradiation. Late G2 cells detect DNA damage lesions and form γ-H2AX foci but fail to activate Chk1. This reflects a lack of DNA double-strand break processing because late G2 cells fail to recruit RPA (replication protein A), ATR (ataxia telangiectasia and Rad3 related), Rad51, or CtIP (C-terminal interacting protein) to sites of radiation-induced damage, events essential for both checkpoint activation and initiation of DNA repair by homologous recombination. Remarkably, inhibition of Akt/PKB (protein kinase B) restores DNA damage processing and Chk1 activation after irradiation in late G2. These data demonstrate a previously unrecognized role for Akt in cell cycle regulation of DNA repair and checkpoint activation. Because Akt/PKB is frequently activated in many tumor types, these findings have important implications for the evolution and therapy of such cancers.

The complex matter of DNA double-strand break detection

2003 ◽  
Vol 31 (1) ◽  
pp. 40-44 ◽  
Author(s):  
J.M. Bradbury ◽  
S.P. Jackson
Keyword(s):  
Dna Damage ◽  
Genome Stability ◽  
Strand Break ◽  
Damage Sensing ◽  
Dna Double Strand Break ◽  
Mre11 Complex ◽  
Damage Response ◽  
Radiation Induced ◽  
Dna Damage Signalling ◽  
Complex Matter

To maintain genomic stability, despite constant exposure to agents that damage DNA, eukaryotic cells have developed elaborate and highly conserved pathways of DNA damage sensing, signalling and repair. In this review, we concentrate mainly on what we know about DNA damage sensing with particular reference to Lcd1p, a yeast protein that functions early in DNA damage signalling, and MDC1 (mediator of DNA damage checkpoint 1), a recently identified human protein that may be involved in recruiting the MRE11 complex to radiation-induced nuclear foci. We describe a model for the DNA damage response in which factors are recruited sequentially to sites of DNA damage to form complexes that can amplify the original signal and propagate it to the multitude of response pathways necessary for genome stability.

scholarly journals Take a Break to Repair: A Dip in the World of Double-Strand Break Repair Mechanisms Pointing the Gaze on Archaea

2021 ◽  
Vol 22 (24) ◽  
pp. 13296
Author(s):  
Mariarosaria De Falco ◽  
Mariarita De Felice
Keyword(s):  
Cell Cycle ◽  
Dna Repair ◽  
Genome Stability ◽  
Developmental Disorders ◽  
Strand Break ◽  
Human Diseases ◽  
Dna Damages ◽  
Dna Repair Mechanisms ◽  
Repair Mechanisms ◽  
Repair Pathways

All organisms have evolved many DNA repair pathways to counteract the different types of DNA damages. The detection of DNA damage leads to distinct cellular responses that bring about cell cycle arrest and the induction of DNA repair mechanisms. In particular, DNA double-strand breaks (DSBs) are extremely toxic for cell survival, that is why cells use specific mechanisms of DNA repair in order to maintain genome stability. The choice among the repair pathways is mainly linked to the cell cycle phases. Indeed, if it occurs in an inappropriate cellular context, it may cause genome rearrangements, giving rise to many types of human diseases, from developmental disorders to cancer. Here, we analyze the most recent remarks about the main pathways of DSB repair with the focus on homologous recombination. A thorough knowledge in DNA repair mechanisms is pivotal for identifying the most accurate treatments in human diseases.

scholarly journals HP1β Chromo Shadow Domain facilitates H2A ubiquitination for BRCA1 recruitment at DNA double-strand breaks

2022 ◽  
Author(s):  
Tej Pandita ◽  
Vijay Kumari Charaka ◽  
Sharmistha Chakraborty ◽  
Chi-Lin Tsai ◽  
Xiaoyan Wang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Genome Stability ◽  
Strand Break ◽  
Dna Double Strand Breaks ◽  
Dsb Repair ◽  
Strand Breaks ◽  
Damage Repair ◽  
Dna Double Strand Break ◽  
Assembly Factor ◽  
Chromo Shadow Domain

Efficient DNA double strand break (DSB) repair by homologous recombination (HR), as orchestrated by histone and non-histone proteins, is critical to genome stability, replication, transcription, and cancer avoidance. Here we report that Heterochromatin Protein1 beta (HP1β) acts as a key component of the HR DNA resection step by regulating BRCA1 enrichment at DNA damage sites, a function largely dependent on the HP1β chromo shadow domain (CSD). HP1β itself is enriched at DSBs within gene-rich regions through a CSD interaction with Chromatin Assembly Factor 1 (CAF1) and HP1β depletion impairs subsequent BRCA1 enrichment. An added interaction of the HP1β CSD with the Polycomb Repressor Complex 1 ubiquitinase component RING1A facilitates BRCA1 recruitment by increasing H2A lysine 118-119 ubiquitination, a marker for BRCA1 recruitment. Our findings reveal that HP1β interactions, mediated through its CSD with RING1A, promote H2A ubiquitination and facilitate BRCA1 recruitment at DNA damage sites, a critical step in DSB repair by the HR pathway. These collective results unveil how HP1β is recruited to DSBs in gene-rich regions and how HP1β subsequently promotes BRCA1 recruitment to further HR DNA damage repair by stimulating CtIP-dependent resection.

scholarly journals RIF1 acts in DNA repair through phosphopeptide recognition of 53BP1

2021 ◽  
Author(s):  
Dheva Setiaputra ◽  
Cristina Escribano-Diaz ◽  
Julia K. Reinert ◽  
Pooja Sadana ◽  
Dali Zong ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Binding Sites ◽  
Binding Protein ◽  
Strand Break ◽  
Chromatin Binding ◽  
Alternative Mode ◽  
Downstream Effectors ◽  
Dna Double Strand Break ◽  
Radiation Induced

SummaryThe chromatin-binding protein 53BP1 promotes DNA repair by orchestrating the recruitment of downstream effectors including PTIP, RIF1 and shieldin to DNA double-strand break sites. While how PTIP recognizes 53BP1 is known, the molecular details of RIF1 recruitment to DNA damage sites remains undefined. Here, we report that RIF1 is a phosphopeptide-binding protein that directly interacts with three phosphorylated 53BP1 epitopes. The RIF1-binding sites on 53BP1 share an essential LxL motif followed by two closely apposed phosphorylated residues. Simultaneous mutation of these sites on 53BP1 abrogates RIF1 accumulation into ionizing radiation-induced foci, but surprisingly only fully compromises 53BP1-dependent DNA repair when an alternative mode of shieldin recruitment to DNA damage sites is also disabled. Intriguingly, this alternative mode of recruitment still depends on RIF1 but does not require its interaction with 53BP1. RIF1 therefore employs phosphopeptide recognition to promote DNA repair but also modifies shieldin action independently of 53BP1 binding.

scholarly journals Guardians of the Genome: BRCA2 and Its Partners

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1229
Author(s):  
Hang Phuong Le ◽  
Wolf-Dietrich Heyer ◽  
Jie Liu
Keyword(s):  
Dna Repair ◽  
Replication Fork ◽  
Genome Stability ◽  
Strand Break ◽  
Fundamental Properties ◽  
Binding Partners ◽  
Dna Double Strand Break ◽  
Interaction Partners ◽  
Brca2 Mutations ◽  
Mechanistic Understanding

The tumor suppressor BRCA2 functions as a central caretaker of genome stability, and individuals who carry BRCA2 mutations are predisposed to breast, ovarian, and other cancers. Recent research advanced our mechanistic understanding of BRCA2 and its various interaction partners in DNA repair, DNA replication support, and DNA double-strand break repair pathway choice. In this review, we discuss the biochemical and structural properties of BRCA2 and examine how these fundamental properties contribute to DNA repair and replication fork stabilization in living cells. We highlight selected BRCA2 binding partners and discuss their role in BRCA2-mediated homologous recombination and fork protection. Improved mechanistic understanding of how BRCA2 functions in genome stability maintenance can enable experimental evidence-based evaluation of pathogenic BRCA2 mutations and BRCA2 pseudo-revertants to support targeted therapy.

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