scholarly journals The Role of Polycomb Group Protein BMI1 in DNA Repair and Genomic Stability

2021 ◽  
Vol 22 (6) ◽  
pp. 2976
Author(s):  
Amira Fitieh ◽  
Andrew J. Locke ◽  
Mobina Motamedi ◽  
Ismail Hassan Ismail
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Gene Silencing ◽  
Strand Break ◽  
Polycomb Group ◽  
Polycomb Group Protein ◽  
Post Translational Modifications ◽  
Dna Damage Signaling ◽  
Dna Double Strand Break ◽  
Group Protein

The polycomb group (PcG) proteins are a class of transcriptional repressors that mediate gene silencing through histone post-translational modifications. They are involved in the maintenance of stem cell self-renewal and proliferation, processes that are often dysregulated in cancer. Apart from their canonical functions in epigenetic gene silencing, several studies have uncovered a function for PcG proteins in DNA damage signaling and repair. In particular, members of the poly-comb group complexes (PRC) 1 and 2 have been shown to recruit to sites of DNA damage and mediate DNA double-strand break repair. Here, we review current understanding of the PRCs and their roles in cancer development. We then focus on the PRC1 member BMI1, discussing the current state of knowledge of its role in DNA repair and genome integrity, and outline how it can be targeted pharmacologically.

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.

scholarly journals SETD2 is required for DNA double-strand break repair and activation of the p53-mediated checkpoint

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Sílvia Carvalho ◽  
Alexandra C Vítor ◽  
Sreerama C Sridhara ◽  
Filipa B Martins ◽  
Ana C Raposo ◽  
...  
Keyword(s):  
Dna Damage ◽  
Strand Break ◽  
Dna Lesions ◽  
Alternative Mechanism ◽  
Dna Double Strand Breaks ◽  
Cell Renal Cell Carcinoma ◽  
Strand Breaks ◽  
Dna Damage Signaling ◽  
Dna Double Strand Break ◽  
Recombination Repair

Histone modifications establish the chromatin states that coordinate the DNA damage response. In this study, we show that SETD2, the enzyme that trimethylates histone H3 lysine 36 (H3K36me3), is required for ATM activation upon DNA double-strand breaks (DSBs). Moreover, we find that SETD2 is necessary for homologous recombination repair of DSBs by promoting the formation of RAD51 presynaptic filaments. In agreement, SETD2-mutant clear cell renal cell carcinoma (ccRCC) cells displayed impaired DNA damage signaling. However, despite the persistence of DNA lesions, SETD2-deficient cells failed to activate p53, a master guardian of the genome rarely mutated in ccRCC and showed decreased cell survival after DNA damage. We propose that this novel SETD2-dependent role provides a chromatin bookmarking instrument that facilitates signaling and repair of DSBs. In ccRCC, loss of SETD2 may afford an alternative mechanism for the inactivation of the p53-mediated checkpoint without the need for additional genetic mutations in TP53.

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 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 Poly(ADP-ribosyl)ation temporally confines SUMO-dependent ataxin-3 recruitment to control DNA double-strand break repair

2021 ◽  
pp. jcs.247809
Author(s):  
Annika Pfeiffer ◽  
Laura K. Herzog ◽  
Martijn S. Luijsterburg ◽  
Rashmi G. Shah ◽  
Magdalena B. Rother ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Time Window ◽  
Strand Break ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Dna Double Strand Break ◽  
Dna Repair Proteins ◽  
Short Time Window ◽  
Short Time

DNA damage-induced SUMOylation serves as a signal for two antagonizing proteins that both stimulate repair of DNA double strand breaks (DSBs). Here, we demonstrate that the SUMO-dependent recruitment of the deubiquitylating enzyme ataxin-3 to DSBs, unlike recruitment of the ubiquitin ligase RNF4, additionally depends on PARP1-mediated poly(ADP-ribosyl)ation (PARylation). The co-dependence of ataxin-3 recruitment on PARylation and SUMOylation temporally confines its presence at DSBs to a short time window directly following detection of the DNA damage. We propose that this mechanism ensures that ataxin-3 prevents the premature removal of DNA repair proteins only during the early phase of the DSB response and does not interfere with the subsequent timely displacement of DNA repair proteins by RNF4. Thus, our data show that PARylation differentially regulates SUMO-dependent recruitment of ataxin-3 and RNF4 to DSBs, explaining how both proteins can play a stimulatory role at DSBs despite their opposing activities.

scholarly journals ADAR-mediated RNA editing of DNA:RNA hybrids is required for DNA double strand break repair

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sonia Jimeno ◽  
Rosario Prados-Carvajal ◽  
María Jesús Fernández-Ávila ◽  
Sonia Silva ◽  
Domenico Alessandro Silvestris ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Rna Editing ◽  
Genomic Stability ◽  
Strand Break ◽  
Dna Lesions ◽  
Dna Breaks ◽  
Dna Double Strand Break ◽  
Editing Enzyme

AbstractThe maintenance of genomic stability requires the coordination of multiple cellular tasks upon the appearance of DNA lesions. RNA editing, the post-transcriptional sequence alteration of RNA, has a profound effect on cell homeostasis, but its implication in the response to DNA damage was not previously explored. Here we show that, in response to DNA breaks, an overall change of the Adenosine-to-Inosine RNA editing is observed, a phenomenon we call the RNA Editing DAmage Response (REDAR). REDAR relies on the checkpoint kinase ATR and the recombination factor CtIP. Moreover, depletion of the RNA editing enzyme ADAR2 renders cells hypersensitive to genotoxic agents, increases genomic instability and hampers homologous recombination by impairing DNA resection. Such a role of ADAR2 in DNA repair goes beyond the recoding of specific transcripts, but depends on ADAR2 editing DNA:RNA hybrids to ease their dissolution.

scholarly journals DNA Damage Repair and DNA Methylation in the Kidney

2019 ◽  
Vol 50 (2) ◽  
pp. 81-91 ◽  
Author(s):  
Kaori Hayashi ◽  
Akihito Hishikawa ◽  
Hiroshi Itoh
Keyword(s):  
Dna Methylation ◽  
Dna Damage ◽  
Dna Repair ◽  
Methylation Status ◽  
Dna Damage Repair ◽  
Strand Break ◽  
Repair System ◽  
Damage Repair ◽  
Dna Double Strand Break ◽  
Cell Type Specific

The DNA repair system is essential for the maintenance of genome integrity and is mainly investigated in the areas of aging and cancer. The DNA repair system is strikingly cell-type specific, depending on the expression of DNA repair factors; therefore, different DNA repair systems may exist in each type of kidney cell. Importance of DNA repair in the kidney is suggested by renal phenotypes caused by both genetic mutations in the DNA repair pathway and increased stimuli of DNA damage. Recently, we reported the importance of DNA double-strand break repair in glomerular podocytes and its involvement in the alteration of DNA methylation status, which regulates podocyte phenotypes. In this review, we summarize the roles of the DNA repair system in the kidneys and possible associations with altered kidney DNA methylation, which have been infrequently reported together. Investigations of DNA damage repair and epigenetic changes in the kidneys may achieve a profound understanding of kidney aging and diseases.

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