Treatment of human cells with 5-aza-dC induces formation of PARP1-DNA covalent adducts at genomic regions targeted by DNMT1.
Abstract The nucleoside analog 5-aza-2'-deoxycytidine (5-aza-dC) is used to treat some hematopoietic malignancies. The mechanism of cell killing depends upon DNMT1, but is otherwise not clearly defined. Here we show that PARP1 forms covalent DNA adducts in human lymphoblast or fibroblasts treated with 5-aza-dC. Some adducts recovered from 5-aza-dC-treated cells have undergone cleavage by apoptotic caspases 3/7. Mapping of PARP1-DNA adducts, by a new method, "Adduct-Seq", demonstrates adduct enrichment at CpG-dense genomic locations that are targets of maintenance methylation by DNMT1. Covalent protein-DN...
Source: DNA Repair - October 2, 2020 Category: Genetics & Stem Cells Authors: Kiianitsa K, Zhang Y, Maizels N Tags: DNA Repair (Amst) Source Type: research

The DNA damage-sensing NER repair factor XPC-RAD23B does not recognize bulky DNA lesions with a missing nucleotide opposite the lesion.
Abstract The Nucleotide Excision Repair (NER) mechanism removes a wide spectrum of structurally different lesions that critically depend on the binding of the DNA damage sensing NER factor XPC-RAD23B (XPC) to the lesions. The bulky mutagenic benzo[a]pyrene diol epoxide metabolite-derived cis- and trans-B[a]P-dG lesions (G*) adopt base-displaced intercalative (cis) or minor groove (trans) conformations in fully paired DNA duplexes with the canonical C opposite G* (G*:C duplexes). While XPC has a high affinity for binding to these DNA lesions in fully complementary double-stranded DNA, we show here that deleting onl...
Source: DNA Repair - October 1, 2020 Category: Genetics & Stem Cells Authors: Feher KM, Kolbanovskiy A, Durandin A, Shim Y, Min JH, Lee YC, Shafirovich V, Mu H, Broyde S, Geacintov NE Tags: DNA Repair (Amst) Source Type: research

Alteration of genetic recombination and double-strand break repair in human cells by progerin expression.
We report that overexpression of progerin correlated with an increase in DSB repair via NHEJ relative to HR, as well as an increased fraction of HR events occurring via gene conversion. Progerin also engendered an apparent increase in spontaneous HR events, with a highly significant shift toward gene conversion events, and an increase in DNA amplification events. Such influences of progerin on DNA transactions may impact genome stability and contribute to aging. PMID: 33010688 [PubMed - as supplied by publisher] (Source: DNA Repair)
Source: DNA Repair - September 27, 2020 Category: Genetics & Stem Cells Authors: Komari CJ, Guttman AO, Carr SR, Trachtenberg TL, Orloff EA, Haas AV, Patrick AR, Chowdhary S, Waldman BC, Waldman AS Tags: DNA Repair (Amst) Source Type: research

Biochemical analysis of TOPBP1 oligomerization.
Abstract TOPBP1 is an important scaffold protein that helps orchestrate the cellular response to DNA damage. Although it has been previously appreciated that TOPBP1 can form oligomers, how this occurs and the functional consequences for oligomerization were not yet known. Here, we use protein binding assays and other biochemical techniques to study how TOPBP1 self associates. TOPBP1 contains 9 copies of the BRCT domain, and we report that a subset of these BRCT domains interact with one another to drive oligomerization. An intact BRCT 2 domain is required for TOPBP1 oligomerization and we find that the BRCT1&2...
Source: DNA Repair - September 20, 2020 Category: Genetics & Stem Cells Authors: Kim A, Montales K, Ruis K, Senebandith H, Gasparyan H, Cowan Q, Michael WM Tags: DNA Repair (Amst) Source Type: research

Modifications and interactions at the R-loop.
Abstract R-loops are tripartite structures consisting of an RNA:DNA hybrid and a displaced single-stranded DNA [1]. They are widespread and occupy up to 5 % of the mammalian genomes [2]. R-loops have a key role in genome stability, and known functions associated with gene regulation, DNA replication, chromatin patterning, immunoglobuline gene recombination and DNA Double-strand break repair [3-7]. Novel methodology, including the application of the S9.6 antibody, have more recently led to detailed knowledge on the genome-wide distribution of the R-loops as well as the identification of the R-loop interactome [8-10...
Source: DNA Repair - September 11, 2020 Category: Genetics & Stem Cells Authors: Li M, Klungland A Tags: DNA Repair (Amst) Source Type: research

Heterotrimeric PCNA increases the activity and fidelity of Dbh, a Y-family translesion DNA polymerase prone to creating single-base deletion mutations.
Abstract Dbh is a Y-family translesion DNA polymerase from Sulfolobus acidocaldarius, an archaeal species that grows in harsh environmental conditions. Biochemically, Dbh displays a distinctive mutational profile, creating single-base deletion mutations at extraordinarily high frequencies (up to 50 %) in specific repeat sequences. In cells, however, Dbh does not appear to contribute significantly to spontaneous frameshifts in these same sequence contexts. This suggests that either the error-prone DNA synthesis activity of Dbh is reduced in vivo and/or Dbh is restricted from replicating these sequences. Here, we te...
Source: DNA Repair - September 5, 2020 Category: Genetics & Stem Cells Authors: Wu Y, Jaremko WJ, Wilson RC, Pata JD Tags: DNA Repair (Amst) Source Type: research

Yeast DNA polymerase η possesses two PIP-like motifs that bind PCNA and Rad6-Rad18 with different specificities.
Yeast DNA polymerase η possesses two PIP-like motifs that bind PCNA and Rad6-Rad18 with different specificities. DNA Repair (Amst). 2020 Sep 06;95:102968 Authors: Ripley BM, Reusch DT, Washington MT Abstract In translesion synthesis (TLS), specialized DNA polymerases, such as polymerase (pol) η and Rev1, are recruited to stalled replication forks. These polymerases form a multi-protein complex with PCNA, Rad6-Rad18, and other specialized polymerases. Pol η interacts with PCNA and Rev1 via a PCNA-interacting protein (PIP) motif in its C-terminal unstructured region. Here we report the disco...
Source: DNA Repair - September 5, 2020 Category: Genetics & Stem Cells Authors: Ripley BM, Reusch DT, Washington MT Tags: DNA Repair (Amst) Source Type: research

Histone H4 LRS mutations can attenuate UV mutagenesis without affecting PCNA ubiquitination or sumoylation.
Abstract UV is a significant environmental agent that damages DNA. Translesion synthesis (TLS) is a DNA damage tolerance pathway that utilizes specialized DNA polymerases to replicate through the damaged DNA, often leading to mutagenesis. In eukaryotic cells, genomic DNA is organized into chromatin that is composed of nucleosomes. To date, if and/or how TLS is regulated by a specific nucleosome feature has been undocumented. We found that mutations of multiple histone H4 residues mostly or entirely embedded in the nucleosomal LRS (loss of ribosomal DNA-silencing) domain attenuate UV mutagenesis in Saccharomyces ce...
Source: DNA Repair - September 2, 2020 Category: Genetics & Stem Cells Authors: Selvam K, Rahman SA, Forrester D, Bao A, Lieu M, Li S Tags: DNA Repair (Amst) Source Type: research

Open gaps in the evolution of the eukaryotic nucleotide excision repair.
Abstract Nucleotide excision repair (NER) is the most versatile DNA repair pathway as it removes different kinds of bulky lesions. Due to its essential role for genome integrity, it has appeared early in the evolution of species. However, most published studies are focused on humans, mice, yeast or bacteria. Considering the large amount of information on genome databases, it is currently possible to retrieve sequences from NER components in many organisms. Therefore, we have characterized the potential orthologs of 10 critical components of the human NER pathway in 12 eukaryotic species by using similarity and str...
Source: DNA Repair - August 22, 2020 Category: Genetics & Stem Cells Authors: Feltrin RDS, Segatto ALA, de Souza TA, Schuch AP Tags: DNA Repair (Amst) Source Type: research

The cerebellar degeneration in ataxia-telangiectasia: A case for genome instability.
Abstract Research on the molecular pathology of genome instability disorders has advanced our understanding of the complex mechanisms that safeguard genome stability and cellular homeostasis at large. Once the culprit genes and their protein products are identified, an ongoing dialogue develops between the research lab and the clinic in an effort to link specific disease symptoms to the functions of the proteins that are missing in the patients. Ataxi A-T elangiectasia (A-T) is a prominent example of this process. A-T's hallmarks are progressive cerebellar degeneration, immunodeficiency, chronic lung disease, canc...
Source: DNA Repair - August 22, 2020 Category: Genetics & Stem Cells Authors: Shiloh Y Tags: DNA Repair (Amst) Source Type: research

PRMT1 is critical to FEN1 expression and drug resistance in lung cancer cells.
Abstract The up-regulation of PRMT1 is critical to the cell growth and cancer progression of lung cancer cells. In our research, we found that PRMT1 is important to the DNA repair ability and drug resistance of lung cancer cells. To demonstrate the functions of PRMT1, we identified Flap endonuclease 1 (FEN1) as a post-translationally modified downstream target protein of PRMT1. As a major component of Base Excision Repair pathway, FEN1 plays an important role in DNA replication and DNA damage repair. However, the detailed mechanism of FEN1 up-regulation in lung cancer cells remains unclear. In our study, we identi...
Source: DNA Repair - August 19, 2020 Category: Genetics & Stem Cells Authors: He L, Hu Z, Sun Y, Zhang M, Zhu H, Jiang L, Zhang Q, Mu D, Zhang J, Gu L, Yang Y, Pan FY, Jia S, Guo Z Tags: DNA Repair (Amst) Source Type: research

P53 in the impaired lungs.
Abstract Our laboratory is focused on investigating the supportive role of P53 towards the maintenance of lung homeostasis. Acute lung injury, acute respiratory distress syndrome, chronic obstructive pulmonary disease, pulmonary fibrosis, bronchial asthma, pulmonary arterial hypertension, pneumonia and tuberculosis are respiratory pathologies, associated with dysfunctions of this endothelium defender (P53). Herein we review the evolving role of P53 towards the aforementioned inflammatory disorders, to potentially reveal new therapeutic possibilities in pulmonary disease. PMID: 32846356 [PubMed - as supplied b...
Source: DNA Repair - August 18, 2020 Category: Genetics & Stem Cells Authors: Uddin MA, Barabutis N Tags: DNA Repair (Amst) Source Type: research

Mechanisms of direct replication restart at stressed replisomes.
PMID: 32853827 [PubMed - as supplied by publisher] (Source: DNA Repair)
Source: DNA Repair - August 15, 2020 Category: Genetics & Stem Cells Authors: Conti BA, Smogorzewska A Tags: DNA Repair (Amst) Source Type: research

C17orf53 is identified as a novel gene involved in inter-strand crosslink repair.
Abstract Ataxia Telangiectasia and Rad3-Related kinase (ATR) is a master regulator of genome maintenance, and participates in DNA replication and various DNA repair pathways. In a genome-wide screen for ATR-dependent fitness genes, we identified a previously uncharacterized gene, C17orf53, whose loss led to hypersensitivity to ATR inhibition. C17orf53 is conserved in vertebrates and is required for efficient cell proliferation. Loss of C17orf53 slowed down DNA replication and led to pronounced interstrand crosslink (ICL) repair defect. We showed that C17orf53 is a ssDNA- and RPA-binding protein and both characteri...
Source: DNA Repair - August 14, 2020 Category: Genetics & Stem Cells Authors: Wang C, Chen Z, Su D, Tang M, Nie L, Zhang H, Feng X, Wang R, Shen X, Srivastava M, McLaughlin ME, Hart T, Li L, Chen J Tags: DNA Repair (Amst) Source Type: research

Pol β gap filling, DNA ligation and substrate-product channeling during base excision repair opposite oxidized 5-methylcytosine modifications.
Pol β gap filling, DNA ligation and substrate-product channeling during base excision repair opposite oxidized 5-methylcytosine modifications. DNA Repair (Amst). 2020 Aug 14;95:102945 Authors: Melike Ç Abstract DNA methylation on cytosine in CpG islands generates 5-methylcytosine (5mC), and further modification of 5mC can result in the oxidized variants 5-hydroxymethyl (5hmC), 5-formyl (5fC), and 5-carboxy (5caC). Base excision repair (BER) is crucial for both genome maintenance and active DNA demethylation of modified cytosine products and involves substrate-product channeling from nucleo...
Source: DNA Repair - August 13, 2020 Category: Genetics & Stem Cells Authors: Melike Ç Tags: DNA Repair (Amst) Source Type: research

Double strand break (DSB) repair in Cyanobacteria: Understanding the process in an ancient organism.
Abstract Cyanobacterial species, Anabaena/Nostoc and Chroococcidiopsis are highly radio-resistant indicating the presence of a robust DNA repair system. However, unlike the establishment of multiple DNA repair pathways in the radio-resistant Deinococcus, research on DNA repair in cyanobacteria has lagged far behind. Being ancient organisms, it is likely that the DNA repair mechanisms have evolved from cyanobacteria to the modern day bacteria. This review focuses on identifying and collating information on the major DNA repair proteins in cyanobacteria including re-annotation of recR and ndk, using Anabaena/Nostoc ...
Source: DNA Repair - August 2, 2020 Category: Genetics & Stem Cells Authors: Rajaram H, Kumar A, Kirti A, Pandey S Tags: DNA Repair (Amst) Source Type: research

Checkpoint adaptation in recombination-deficient cells drives aneuploidy and resistance to genotoxic agents.
Abstract Human cancers frequently harbour mutations in DNA repair genes, rendering the use of DNA damaging agents as an effective therapeutic intervention. As therapy-resistant cells often arise, it is important to better understand the molecular pathways that drive resistance in order to facilitate the eventual targeting of such processes. We employ recombination-defective diploid yeast as a model to demonstrate that, in response to genotoxic challenges, nearly all cells eventually undergo checkpoint adaptation, resulting in the generation of aneuploid cells with whole chromosome losses that have acquired resista...
Source: DNA Repair - July 29, 2020 Category: Genetics & Stem Cells Authors: Vydzhak O, Bender K, Klermund J, Busch A, Reimann S, Luke B Tags: DNA Repair (Amst) Source Type: research

Translesion synthesis of 6-nitrochrysene-derived 2'-deoxyadenosine adduct in human cells.
In this study, we have investigated replication of N-(dA-8-yl)-6-AC in human embryonic kidney (HEK 293T) cells and the roles of translesion synthesis (TLS) DNA polymerases in bypassing it. Replication of a plasmid containing a single site-specific N-(dA-8-yl)-6-AC adduct in HEK 293 T cells showed that human DNA polymerase (hPol) η and hPol κ played important roles in bypassing the adduct, since TLS efficiency was reduced to 26 % in the absence of these two polymerases compared to 83 % in polymerase-competent HEK 293T cells. The progeny from HEK 293T cells provided 12.7 % mutants predominantly containing A→T ...
Source: DNA Repair - July 17, 2020 Category: Genetics & Stem Cells Authors: Powell BV, Bacurio JHT, Basu AK Tags: DNA Repair (Amst) Source Type: research

Novel TALEN-generated mCitrine-FANCD2 fusion reporter mouse model for in vivo research of DNA damage response.
In this study, we employed TALENs to generate a reporter fusion protein expressed from its native promoter. For monitoring DNA damage response, we generated a mouse line expressing a mCitrine-tagged version of the FANCD2 protein, involved in DNA damage response and repair, and the Fanconi anemia (FA) pathway. This model could be a valuable tool for in vivo investigation of DNA damage. PMID: 32717583 [PubMed - as supplied by publisher] (Source: DNA Repair)
Source: DNA Repair - July 15, 2020 Category: Genetics & Stem Cells Authors: Sabol M, Akbudak MA, Fricova D, Beck I, Sedlacek R Tags: DNA Repair (Amst) Source Type: research

XPA deficiency affects the ubiquitin-proteasome system function.
In conclusion, stress response activation occurs in XPA-deficient cells under oxidative stress; however, these cells fail to activate the UPS cytoprotective response, which may contribute to XPA patient's phenotypes. PMID: 32693352 [PubMed - as supplied by publisher] (Source: DNA Repair)
Source: DNA Repair - July 15, 2020 Category: Genetics & Stem Cells Authors: de Sousa Leal AM, de Azevedo Medeiros LB, Muñoz-Cadavid CO, de Paula Oliveira R, de Souza Timóteo AR, de Oliveira AHS, Luis Fonseca Faustino A, da Silva VL, de Souza SJ, Braz Petta Lajus T, de Melo Campos JTA, Agnez-Lima LF Tags: DNA Repair (Amst) Source Type: research

Debulking of topoisomerase DNA-protein crosslinks (TOP-DPC) by the proteasome, non-proteasomal and non-proteolytic pathways.
Abstract Topoisomerases play a pivotal role in ensuring DNA metabolisms during replication, transcription and chromosomal segregation. To manage DNA topology, topoisomerases generate break(s) in the DNA backbone by forming transient enzyme-DNA cleavage complexes (TOPcc) with phosphotyrosyl linkages between DNA ends and topoisomerase catalytic tyrosyl residues. Topoisomerases have been identified as the cellular targets of a variety of anti-cancer drugs (e.g. topotecan, irinotecan, etoposide and doxorubicin, and antibiotics (e.g. ciprofloxacin and levofloxacin). These drugs, as well as other exogenous and endogenou...
Source: DNA Repair - July 9, 2020 Category: Genetics & Stem Cells Authors: Sun Y, Saha LK, Saha S, Jo U, Pommier Y Tags: DNA Repair (Amst) Source Type: research

Deciphering the role of distinct DNA-PK phosphorylations at collapsed replication forks.
Abstract It has recently been established that the marked sensitivity of ATM deficient cells to topoisomerase poisons like camptothecin (Cpt) results from unrestrained end-joining of DNA ends at collapsed replication forks that is mediated by the non-homologous end joining [NHEJ] pathway and results in the induction of copious numbers of genomic alterations, termed "toxic NHEJ". Ablation of core components of the NHEJ pathway reverses the Cpt sensitivity of ATM deficient cells, but inhibition of DNA-PKcs does not. Here, we show that complete ablation of DNA-PKcs partially reverses the Cpt sensitivity of ...
Source: DNA Repair - July 7, 2020 Category: Genetics & Stem Cells Authors: Neal JA, Dunger K, Geith K, Meek K Tags: DNA Repair (Amst) Source Type: research

Structural biology of DNA abasic site protection by SRAP proteins.
Abstract Abasic (AP) sites are one of the most frequently occurring types of DNA damage. They lead to DNA strand breaks, interstrand DNA crosslinks, and block transcription and replication. Mutagenicity of AP sites arises from translesion synthesis (TLS) by error-prone bypass polymerases. Recently, a new cellular response to AP sites was discovered, in which the protein HMCES (5-hydroxymethlycytosine (5hmC) binding, embryonic stem cell-specific) forms a stable, covalent DNA-protein crosslink (DPC) to AP sites at stalled replication forks. The stability of the HMCES-DPC prevents strand cleavage by endonucleases and...
Source: DNA Repair - June 28, 2020 Category: Genetics & Stem Cells Authors: Amidon KM, Eichman BF Tags: DNA Repair (Amst) Source Type: research

Methylation of the central transcriptional regulator KLF4 by PRMT5 is required for DNA end resection and recombination.
hez MS, Gómez-Cabello D, Huertas P Abstract Cell fitness and survival upon exposure to DNA damage depends on the repair of DNA lesions. Interestingly, cellular identity does affect and finetunes such response, although the molecular basis of such differences between tissues and cell types is not well understood. Thus, a possibility is that DNA repair itself is controlled by the mechanisms that govern cell identity. Here we show that the KLF4, involved in cellular homeostasis, proliferation, cell reprogramming and cancer development, directly regulates resection and homologous recombination proficiency. Inde...
Source: DNA Repair - June 26, 2020 Category: Genetics & Stem Cells Authors: Checa-Rodríguez C, Cepeda-García C, Ramón J, López-Saavedra A, Balestra FR, Domínguez-Sánchez MS, Gómez-Cabello D, Huertas P Tags: DNA Repair (Amst) Source Type: research

Twenty years of t-loops: A case study for the importance of collaboration in molecular biology.
Griffith JD Abstract Collaborative studies open doors to breakthroughs otherwise unattainable by any one laboratory alone. Here we describe the initial collaboration between the Griffith and de Lange laboratories that led to thinking about the telomere as a DNA template for homologous recombination, the proposal of telomere looping, and the first electron micrographs of t-loops. This was followed by collaborations that revealed t-loops across eukaryotic phyla. The Griffith and Tomáška/Nosek collaboration revealed circular telomeric DNA (t-circles) derived from the linear mitochondrial chromosomes of ...
Source: DNA Repair - June 25, 2020 Category: Genetics & Stem Cells Authors: Tomáška Ľ, Cesare AJ, AlTurki TM, Griffith JD Tags: DNA Repair (Amst) Source Type: research

The recent advances in non-homologous end-joining through the lens of lymphocyte development.
Abstract Lymphocyte development requires ordered assembly and subsequent modifications of the antigen receptor genes through V(D)J recombination and Immunoglobulin class switch recombination (CSR), respectively. While the programmed DNA cleavage events are initiated by lymphocyte-specific factors, the resulting DNA double-strand break (DSB) intermediates activate the ATM kinase-mediated DNA damage response (DDR) and rely on the ubiquitously expressed classical non-homologous end-joining (cNHEJ) pathway including the DNA-dependent protein kinase (DNA-PK), and, in the case of CSR, also the alternative end-joining (A...
Source: DNA Repair - June 24, 2020 Category: Genetics & Stem Cells Authors: Wang XS, Lee BJ, Zha S Tags: DNA Repair (Amst) Source Type: research

TREX1 - Apex predator of cytosolic DNA metabolism.
Abstract The cytosolic Three prime Repair EXonuclease 1 (TREX1) is a powerful DNA-degrading enzyme required for clearing cytosolic DNA to prevent aberrant inflammation and autoimmunity. In the absence of TREX1 activity, cytosolic DNA pattern recognition receptors of the innate immune system are constitutively activated by undegraded TREX1 substrates. This triggers a chronic inflammatory response in humans expressing mutant TREX1 alleles, eliciting a spectrum of rare autoimmune diseases dependent on the nature of the mutation. The precise origins of cytosolic DNA targeted by TREX1 continue to emerge, but DNA emergi...
Source: DNA Repair - June 11, 2020 Category: Genetics & Stem Cells Authors: Simpson SR, Hemphill WO, Hudson T, Perrino FW Tags: DNA Repair (Amst) Source Type: research

Reported DNA repair protein CECR2, which is associated with neural tube defects in mice, is not required for double-strand break repair in primary neurospheres.
PMID: 32570002 [PubMed - as supplied by publisher] (Source: DNA Repair)
Source: DNA Repair - June 2, 2020 Category: Genetics & Stem Cells Authors: Elliott J, Norton KA, Niri FH, McDermid HE Tags: DNA Repair (Amst) Source Type: research

Mechanisms of DNA repair in Trypanosoma cruzi: What do we know so far?
Abstract Trypanosoma cruzi is the etiological agent of Chagas Disease, which affects 6-7 million people worldwide. Since the early stages of infection and throughout its life cycle, the parasite is exposed to several genotoxic agents. Furthermore, DNA damage is also part of the mechanism of action of at least a few trypanocidal drugs, including Benznidazole. Thus, it is paramount for the parasite to count on an efficient DNA repair machinery to guarantee genome integrity and survival. The present work provides an up-to-date review of both the conserved and peculiar DNA repair mechanisms described in T. cruzi again...
Source: DNA Repair - May 28, 2020 Category: Genetics & Stem Cells Authors: Rose E, Carvalho JL, Hecht M Tags: DNA Repair (Amst) Source Type: research

Role of mtDNA disturbances in the pathogenesis of Alzheimer's and Parkinson's disease.
acute;kora D, Mikšátková L, Martásek P, Jakubek M Abstract Neurodegenerative diseases (e.g. Alzheimer's and Parkinson's disease) are becoming increasingly problematic to healthcare systems. Therefore, their underlying mechanisms are trending topics of study in medicinal research. Numerous studies have evidenced a strong association between mitochondrial DNA disturbances (e.g. oxidative damage, mutations, and methylation shifts) and the initiation and progression of neurodegenerative diseases. Therefore, this review discusses the risk and development of neurodegenerative diseases in term...
Source: DNA Repair - May 20, 2020 Category: Genetics & Stem Cells Authors: Antonyová V, Kejík Z, Brogyányi T, Kaplánek R, Pajková M, Talianová V, Hromádka R, Masařík M, Sýkora D, Mikšátková L, Martásek P, Jakubek M Tags: DNA Repair (Amst) Source Type: research

MutS α deficiency increases tolerance to DNA damage in yeast lacking postreplication repair.
In this study, we identified a novel link between mismatch repair (MMR) genes and postreplication repair (PRR) in Saccharomyces cerevisiae. Strains lacking Rad5 (HLTF in mammals), a protein important for restarting stalled replication forks in the error-free PRR pathway, were supersensitive to the DNA methylating agent methyl methanesulfonate (MMS). Deletion of the mismatch repair genes, MSH2 or MSH6, which together constitutes the MutSα complex, partially suppressed the MMS super-sensitivity of the rad5Δ strain. Deletion of MSH2 also suppressed the MMS sensitivity of mms2Δ, which acts together with Rad5 ...
Source: DNA Repair - May 20, 2020 Category: Genetics & Stem Cells Authors: Berg IL, Persson JO, Åström SU Tags: DNA Repair (Amst) Source Type: research

Hypermutation in single-stranded DNA.
Abstract Regions of genomic DNA can become single-stranded in the course of normal replication and transcription as well as during DNA repair. Abnormal repair and replication intermediates can contain large stretches of persistent single-stranded DNA, which is extremely vulnerable to DNA damaging agents and hypermutation. Since such single-stranded DNA spans only a fraction of the genome at a given instance, hypermutation in these regions leads to tightly-spaced mutation clusters. This phenomenon of hypermutation in single-stranded DNA has been documented in several experimental models as well as in cancer genomes...
Source: DNA Repair - May 17, 2020 Category: Genetics & Stem Cells Authors: Saini N, Gordenin DA Tags: DNA Repair (Amst) Source Type: research

Corrigendum to "The Ku-dependent non-homologous end-joining but not other repair pathway is inhibited by high linear energy transfer ionizing radiation" [DNA Repair 27 (2008) 725-733].
Corrigendum to "The Ku-dependent non-homologous end-joining but not other repair pathway is inhibited by high linear energy transfer ionizing radiation" [DNA Repair 27 (2008) 725-733]. DNA Repair (Amst). 2020 May 11;:102857 Authors: Wang H, Wang X, Zhang P, Wang Y PMID: 32409156 [PubMed - as supplied by publisher] (Source: DNA Repair)
Source: DNA Repair - May 10, 2020 Category: Genetics & Stem Cells Authors: Wang H, Wang X, Zhang P, Wang Y Tags: DNA Repair (Amst) Source Type: research

Size-dependent antirecombinogenic effect of short spacers on palindrome recombinogenicity.
ec IK Abstract Palindromic sequences in DNA can instigate genetic recombination and genome instability, which can result in devastating conditions such as the Emmanuel syndrome. Palindrome recombinogenicity increases with its size and sequence similarity between palindrome arms, while quasipalindromes with long spacers are less recombinogenic. However, the minimal spacer length, which could reduce or abolish palindrome recombinogenicity in the eukaryotic genome, was never determined. Therefore, we constructed a series of palindromes containing spacers of lengths ranging from 0 (perfect palindrome) to 10 bp and tes...
Source: DNA Repair - May 2, 2020 Category: Genetics & Stem Cells Authors: Svetec Miklenić M, Gatalica N, Matanović A, Žunar B, Štafa A, Lisnić B, Svetec IK Tags: DNA Repair (Amst) Source Type: research

Redirecting E2F1 to TA-p73 improves cancer therapy through apoptotic induction.
PMID: 32388489 [PubMed - as supplied by publisher] (Source: DNA Repair)
Source: DNA Repair - April 27, 2020 Category: Genetics & Stem Cells Authors: El Dika M Tags: DNA Repair (Amst) Source Type: research

New complexities of SOS-induced "untargeted" mutagenesis in Escherichia coli as revealed by mutation accumulation and whole-genome sequencing.
New complexities of SOS-induced "untargeted" mutagenesis in Escherichia coli as revealed by mutation accumulation and whole-genome sequencing. DNA Repair (Amst). 2020 Apr 18;90:102852 Authors: Niccum BA, Coplen CP, Lee H, Mohammed Ismail W, Tang H, Foster PL Abstract When its DNA is damaged, Escherichia coli induces the SOS response, which consists of about 40 genes that encode activities to repair or tolerate the damage. Certain alleles of the major SOS-control genes, recA and lexA, cause constitutive expression of the response, resulting in an increase in spontaneous mutations. These mutat...
Source: DNA Repair - April 17, 2020 Category: Genetics & Stem Cells Authors: Niccum BA, Coplen CP, Lee H, Mohammed Ismail W, Tang H, Foster PL Tags: DNA Repair (Amst) Source Type: research

New insights into the regulation of DNA-Protein Crosslink Repair by the Aspartic Protease Ddi1 in yeast.
PMID: 32330640 [PubMed - as supplied by publisher] (Source: DNA Repair)
Source: DNA Repair - April 14, 2020 Category: Genetics & Stem Cells Authors: El Dika M Tags: DNA Repair (Amst) Source Type: research

Cross-linking of the DNA repair protein O6-alkylguanine DNA alkyltransferase to DNA in the presence of cisplatin.
Abstract 1,1,2,2-cis-diamminedichloroplatinum (II) (cisplatin) is a chemotherapeutic agent widely used in the clinic to treat various cancers. The antitumor activity of cisplatin is generally attributed to its ability to form intrastrand and interstrand DNA-DNA cross-links via sequential platination of two nucleophilic sites within the DNA duplex. However, cisplatin also induces DNA- protein lesions (DPCs) that may contribute to its biological effects due to their ability to block DNA replication and transcription. We previously reported that over 250 nuclear proteins including high mobility group proteins, histon...
Source: DNA Repair - March 18, 2020 Category: Genetics & Stem Cells Authors: Ming X, Michaelson-Richie ED, Groehler AS, Villalta PW, Campbell C, Tretyakova NY Tags: DNA Repair (Amst) Source Type: research

Excision repair of topoisomerase DNA-protein crosslinks (TOP-DPC).
Abstract Topoisomerases are essential enzymes solving DNA topological problems such as supercoils, knots and catenanes that arise from replication, transcription, chromatin remodeling and other nucleic acid metabolic processes. They are also the targets of widely used anticancer drugs (e.g. topotecan, irinotecan, enhertu, etoposide, doxorubicin, mitoxantrone) and fluoroquinolone antibiotics (e.g. ciprofloxacin and levofloxacin). Topoisomerases manipulate DNA topology by cleaving one DNA strand (TOP1 and TOP3 enzymes) or both in concert (TOP2 enzymes) through the formation of transient enzyme-DNA cleavage complexes...
Source: DNA Repair - March 6, 2020 Category: Genetics & Stem Cells Authors: Sun Y, Saha S, Wang W, Saha LK, Huang SN, Pommier Y Tags: DNA Repair (Amst) Source Type: research

Chromosomal aberration dynamics through the cell cycle.
Abstract DNA double-strand breaks are the crucial lesions underlying the formation of chromosomal aberrations, their formation and kinetics have been extensively studied, although dynamics of the repair process has not been fully understood. By using a combination of different cytogenetic techniques to analyze cells in G0, G2 and M phase, in the present study we perform a follow up study of the dynamics of different radiation induced chromosomal aberrations. Data here presented show that in G0 phase chromosome fragments lacking telomere signals (incomplete chromosome elements, ICE) show a slow repair, but when rep...
Source: DNA Repair - March 5, 2020 Category: Genetics & Stem Cells Authors: Pujol-Canadell M, Puig R, Armengol G, Barrios L, Barquinero JF Tags: DNA Repair (Amst) Source Type: research

Chromosome breaks generated by low doses of ionizing radiation in G2-phase are processed exclusively by gene conversion.
We reported that during G2-phase, where all pathways are active, GC engages in the processing of almost 50 % of DSBs, at low DSB-loads in the genome, and that this contribution rapidly drops to nearly zero with increasing DSB-loads. At the transition between these two extremes, SSA and alt-EJ compensate, but at extremely high DSB-loads resection-dependent pathways are suppressed and c-NHEJ remains mainly active. We inquired whether in this processing framework all DSBs have similar fates. Here, we analyze in G2-phase the processing of a subset of DSBs defined by their ability to break chromosomes. Our results reveal an abs...
Source: DNA Repair - February 26, 2020 Category: Genetics & Stem Cells Authors: Soni A, Murmann-Konda T, Siemann-Loekes M, Pantelias GE, Iliakis G Tags: DNA Repair (Amst) Source Type: research

Helicobacter pylori severely reduces expression of DNA repair proteins PMS2 and ERCC1 in gastritis and gastric cancer.
Abstract Gastric cancers are the third leading cause of cancer mortality in the world. Helicobacter pylori causes over 60 % of all stomach cancers. Colonization of the gastric mucosa by H. pylori results in increased DNA damage. Repair of DNA damage may also be reduced by H. pylori infection. Reduced DNA repair in combination with increased DNA damage can cause carcinogenic mutations. During progression to gastric cancer, gastric epithelium goes through stages of increasing pathology. Determining the levels of DNA repair enzymes during progression to gastric cancer could illuminate treatment approaches. Our aim is...
Source: DNA Repair - February 25, 2020 Category: Genetics & Stem Cells Authors: Raza Y, Ahmed A, Khan A, Chishti AA, Akhter SS, Mubarak M, Bernstein C, Zaitlin B, Kazmi SU Tags: DNA Repair (Amst) Source Type: research

Two main mutational processes operate in the absence of DNA mismatch repair.
uuml;ts D Abstract The analysis of tumour genome sequences has demonstrated high rates of base substitution mutagenesis upon the inactivation of DNA mismatch repair (MMR), and the resulting somatic mutations in MMR deficient tumours appear to significantly enhance the response to immune therapy. A handful of different algorithmically derived base substitution mutation signatures have been attributed to MMR deficiency in tumour somatic mutation datasets. In contrast, mutation data obtained from whole genome sequences of isogenic wild type and MMR deficient cell lines in this study, as well as from published sources...
Source: DNA Repair - February 24, 2020 Category: Genetics & Stem Cells Authors: Németh E, Lovrics A, Gervai JZ, Seki M, Rospo G, Bardelli A, Szüts D Tags: DNA Repair (Amst) Source Type: research

The importance of Ile716 toward the mutagenicity of 8-Oxo-2'-deoxyguanosine with Bacillus fragment DNA polymerase.
Abstract 8-oxo-2'-deoxyguanosine (OdG) is a prominent DNA lesion that can direct the incorporation of dCTP or dATP during replication. As the latter reaction can lead to mutation, the ratio of dCTP/dATP incorporation can significantly affect the mutagenic potential of OdG. Previous work with the A-family polymerase BF and seven analogues of OdG identified a major groove amino acid, Ile716, which likely influences the dCTP/dATP incorporation ratio opposite OdG. To further probe the importance of this amino acid, dCTP and dATP incorporations opposite the same seven analogues were tested with two BF mutants, I716M an...
Source: DNA Repair - February 19, 2020 Category: Genetics & Stem Cells Authors: Hamm ML, Garcia AA, Gilbert R, Johri M, Ricart M, Sholes SL, Murray-Nerger LA, Wu EY Tags: DNA Repair (Amst) Source Type: research

The "adductome": A limited repertoire of adducted proteins in human cells.
The "adductome": A limited repertoire of adducted proteins in human cells. DNA Repair (Amst). 2020 Feb 19;89:102825 Authors: Kiianitsa K, Maizels N Abstract Proteins form adducts with nucleic acids in a variety of contexts, and these adducts may be cytotoxic if not repaired. Here we apply a proteomic approach to identification of proteins adducted to DNA or RNA in normally proliferating cells. This approach combines RADAR fractionation of proteins covalently bound to nucleic acids with quantitative mass spectrometry (MS). We demonstrate that "RADAR-MS" can quantify induction of TOP...
Source: DNA Repair - February 18, 2020 Category: Genetics & Stem Cells Authors: Kiianitsa K, Maizels N Tags: DNA Repair (Amst) Source Type: research

DNA-protein crosslink formation by endogenous aldehydes and AP sites.
Abstract Covalent binding between proteins and a DNA strand produces DNA-protein crosslinks (DPC). DPC are one of the most deleterious types of DNA damage, leading to the blockage of DNA replication and transcription. Both DNA lesions and endogenous products with carbonyl functional groups can produce DPC in genomic DNA under normal physiological conditions. For example, formaldehyde, the most abundant endogenous human carcinogen, and apurinic/apyrimidinic (AP) sites, the most common type of endogenous DNA lesions, has been shown to crosslink proteins and/or DNA through their carbonyl functional groups. Unfortunat...
Source: DNA Repair - February 9, 2020 Category: Genetics & Stem Cells Authors: Nakamura J, Nakamura M Tags: DNA Repair (Amst) Source Type: research

The dichotomous effects of caffeine on homologous recombination in mammalian cells.
This study was initiated to examine the effects of caffeine on the DNA damage response (DDR) and homologous recombination (HR) in mammalian cells. A 5 mM caffeine treatment caused the cell cycle to stall at G2/M and cells eventually underwent apoptosis. Caffeine exposure also induced a strong DDR along with subsequent activation of wildtype p53 protein. An unexpected observation was the caffeine-induced depletion of Rad51 (and Brca2) proteins. Consequently, caffeine-treated cells were expected to be inefficient in HR. However, a dichotomy in the HR response of cells to caffeine treatment was revealed. Caffeine treatment ...
Source: DNA Repair - February 6, 2020 Category: Genetics & Stem Cells Authors: Magwood AC, Mundia MM, Pladwig SM, Mosser DD, Baker MD Tags: DNA Repair (Amst) Source Type: research

Function and evolution of the DNA-protein crosslink proteases Wss1 and SPRTN.
Abstract Covalent DNA-protein crosslinks (DPCs) are highly toxic DNA adducts, which interfere with faithful DNA replication. The proteases Wss1 and SPRTN degrade DPCs and have emerged as crucially important DNA repair enzymes. Their protective role has been described in various model systems ranging from yeasts, plants, worms and flies to mice and humans. Loss of DPC proteases results in genome instability, cellular arrest, premature ageing and cancer predisposition. Here we discuss recent insights into the function and molecular mechanism of these enzymes. Furthermore, we present an in-depth phylogenetic analysis...
Source: DNA Repair - February 5, 2020 Category: Genetics & Stem Cells Authors: Reinking HK, Hofmann K, Stingele J Tags: DNA Repair (Amst) Source Type: research

Proofreading of single nucleotide insertion/deletion replication errors analyzed by MALDI-TOF mass spectrometry assay.
We examined proofreading of DNAs containing indel errors at various positions of the primer-template junction. We found that indel errors located 1-5-nucleotides (nt) from the primer terminus can be proofread efficiently, while insertion/deletions at 6-nt from the 3' end are partially corrected and extended. Indels located 7-9-nt from the primer terminus escape proofreading and are elongated by polymerase. The possible underlying mechanisms of these observations are discussed in the context of the polymerase and primer-template junction interactions via a structure analysis. PMID: 32036259 [PubMed - as supplied by pub...
Source: DNA Repair - January 29, 2020 Category: Genetics & Stem Cells Authors: Chang HL, Su KY, Goodman SD, Chou NA, Lin KC, Cheng WC, Lin LI, Chang SY, Fang WH Tags: DNA Repair (Amst) Source Type: research

Higher chromosome stability in embryonic neural stem and progenitor cells than in fibroblasts in response to acute or chronic genotoxic stress.
Abstract High fidelity of genetic transmission in neural stem and progenitor cells (NSPCs) has been long time considered to be crucial for brain development and homeostasis. However, recent studies have identified recurrent DSB clusters in dividing NSPCs, which may underlie the diversity of neuronal cell types. This raised the interest in understanding how NSPCs sense and repair DSBs and how this mechanism could be altered by environmental genotoxic stress caused by pollutants or ionizing radiation. Here, we show that embryonic mouse neural stem and progenitor cells (NSPCs) have significantly higher capacity than ...
Source: DNA Repair - January 27, 2020 Category: Genetics & Stem Cells Authors: Mokrani S, Granotier-Beckers C, Etienne O, Kortulewski T, Grisolia C, de Villartay JP, Boussin FD Tags: DNA Repair (Amst) Source Type: research