bims-nutges Biomed News
on Nucleolar transcription and genomic stability
Issue of 2021‒08‒22
eight papers selected by
Kanwal Tariq
Stockholm University
  1. Structural basis for proficient oxidized ribonucleotide insertion in double strand break repair.
  2. Histone lysine modifying enzymes and their critical roles in DNA double-strand break repair.
  3. RNF168-mediated localization of BARD1 recruits the BRCA1-PALB2 complex to DNA damage.
  4. Histone H4 lysine 20 mono-methylation directly facilitates chromatin openness and promotes transcription of housekeeping genes.
  5. Heterogeneity of DNA damage incidence and repair in different chromatin contexts.
  6. Role of histone acetyltransferases MOF and Tip60 in genome stability.
  7. Toxic R-loops: Cause or consequence of replication stress?
  8. G-quadruplexes in the mitochondrial genome - a cause for instability.
  1. Nat Commun. 2021 Aug 20. 12(1): 5055
    Structural basis for proficient oxidized ribonucleotide insertion in double strand break repair.
    Joonas A Jamsen, Akira Sassa, Lalith Perera, David D Shock, William A Beard, Samuel H Wilson.
      Reactive oxygen species (ROS) oxidize cellular nucleotide pools and cause double strand breaks (DSBs). Non-homologous end-joining (NHEJ) attaches broken chromosomal ends together in mammalian cells. Ribonucleotide insertion by DNA polymerase (pol) μ prepares breaks for end-joining and this is required for successful NHEJ in vivo. We previously showed that pol μ lacks discrimination against oxidized dGTP (8-oxo-dGTP), that can lead to mutagenesis, cancer, aging and human disease. Here we reveal the structural basis for proficient oxidized ribonucleotide (8-oxo-rGTP) incorporation during DSB repair by pol μ. Time-lapse crystallography snapshots of structural intermediates during nucleotide insertion along with computational simulations reveal substrate, metal and side chain dynamics, that allow oxidized ribonucleotides to escape polymerase discrimination checkpoints. Abundant nucleotide pools, combined with inefficient sanitization and repair, implicate pol μ mediated oxidized ribonucleotide insertion as an emerging source of widespread persistent mutagenesis and genomic instability.
    DOI:  https://doi.org/10.1038/s41467-021-24486-x
  2. DNA Repair (Amst). 2021 Aug 12. pii: S1568-7864(21)00162-2. [Epub ahead of print]107 103206
    Histone lysine modifying enzymes and their critical roles in DNA double-strand break repair.
    Jun Zhang, Xiaopeng Lu, Sara MoghaddamKohi, Lei Shi, Xingzhi Xu, Wei-Guo Zhu.
      Cells protect the integrity of the genome against DNA double-strand breaks through several well-characterized mechanisms including nonhomologous end-joining repair, homologous recombination repair, microhomology-mediated end-joining and single-strand annealing. However, aberrant DNA damage responses (DDRs) lead to genome instability and tumorigenesis. Clarification of the mechanisms underlying the DDR following lethal damage will facilitate the identification of therapeutic targets for cancer. Histones are small proteins that play a major role in condensing DNA into chromatin and regulating gene function. Histone modifications commonly occur in several residues including lysine, arginine, serine, threonine and tyrosine, which can be acetylated, methylated, ubiquitinated and phosphorylated. Of these, lysine modifications have been extensively explored during DDRs. Here, we focus on discussing the roles of lysine modifying enzymes involved in acetylation, methylation, and ubiquitination during the DDR. We provide a comprehensive understanding of the basis of potential epigenetic therapies driven by histone lysine modifications.
    Keywords:  Acetylation; DNA damage response; Enzymes; Histone lysine modification; Methylation; Ubiquitination
    DOI:  https://doi.org/10.1016/j.dnarep.2021.103206
  3. Nat Commun. 2021 08 18. 12(1): 5016
    RNF168-mediated localization of BARD1 recruits the BRCA1-PALB2 complex to DNA damage.
    John J Krais, Yifan Wang, Pooja Patel, Jayati Basu, Andrea J Bernhardy, Neil Johnson.
      DNA damage prompts a diverse range of alterations to the chromatin landscape. The RNF168 E3 ubiquitin ligase catalyzes the mono-ubiquitination of histone H2A at lysine (K)13/15 (mUb-H2A), forming a binding module for DNA repair proteins. BRCA1 promotes homologous recombination (HR), in part, through its interaction with PALB2, and the formation of a larger BRCA1-PALB2-BRCA2-RAD51 (BRCA1-P) complex. The mechanism by which BRCA1-P is recruited to chromatin surrounding DNA breaks is unclear. In this study, we reveal that an RNF168-governed signaling pathway is responsible for localizing the BRCA1-P complex to DNA damage. Using mice harboring a Brca1CC (coiled coil) mutation that blocks the Brca1-Palb2 interaction, we uncovered an epistatic relationship between Rnf168- and Brca1CC alleles, which disrupted development, and reduced the efficiency of Palb2-Rad51 localization. Mechanistically, we show that RNF168-generated mUb-H2A recruits BARD1 through a BRCT domain ubiquitin-dependent recruitment motif (BUDR). Subsequently, BARD1-BRCA1 accumulate PALB2-RAD51 at DNA breaks via the CC domain-mediated BRCA1-PALB2 interaction. Together, these findings establish a series of molecular interactions that connect the DNA damage signaling and HR repair machinery.
    DOI:  https://doi.org/10.1038/s41467-021-25346-4
  4. Nat Commun. 2021 Aug 20. 12(1): 4800
    Histone H4 lysine 20 mono-methylation directly facilitates chromatin openness and promotes transcription of housekeeping genes.
    Muhammad Shoaib, Qinming Chen, Xiangyan Shi, Nidhi Nair, Chinmayi Prasanna, Renliang Yang, David Walter, Klaus S Frederiksen, Hjorleifur Einarsson, J Peter Svensson, Chuan Fa Liu, Karl Ekwall, Mads Lerdrup, Lars Nordenskiöld, Claus S Sørensen.
      Histone lysine methylations have primarily been linked to selective recruitment of reader or effector proteins that subsequently modify chromatin regions and mediate genome functions. Here, we describe a divergent role for histone H4 lysine 20 mono-methylation (H4K20me1) and demonstrate that it directly facilitates chromatin openness and accessibility by disrupting chromatin folding. Thus, accumulation of H4K20me1 demarcates highly accessible chromatin at genes, and this is maintained throughout the cell cycle. In vitro, H4K20me1-containing nucleosomal arrays with nucleosome repeat lengths (NRL) of 187 and 197 are less compact than unmethylated (H4K20me0) or trimethylated (H4K20me3) arrays. Concordantly, and in contrast to trimethylated and unmethylated tails, solid-state NMR data shows that H4K20 mono-methylation changes the H4 conformational state and leads to more dynamic histone H4-tails. Notably, the increased chromatin accessibility mediated by H4K20me1 facilitates gene expression, particularly of housekeeping genes. Altogether, we show how the methylation state of a single histone H4 residue operates as a focal point in chromatin structure control. While H4K20me1 directly promotes chromatin openness at highly transcribed genes, it also serves as a stepping-stone for H4K20me3-dependent chromatin compaction.
    DOI:  https://doi.org/10.1038/s41467-021-25051-2
  5. DNA Repair (Amst). 2021 Aug 13. pii: S1568-7864(21)00166-X. [Epub ahead of print]107 103210
    Heterogeneity of DNA damage incidence and repair in different chromatin contexts.
    Pedro Ortega, Belén Gómez-González, Andrés Aguilera.
      It has been long known that some regions of the genome are more susceptible to damage and mutagenicity than others. Recent advances have determined a critical role of chromatin both in the incidence of damage and in its repair. Thus, chromatin arises as a guardian of the stability of the genome, which is altered in cancer cells. In this review, we focus into the mechanisms by which chromatin influences the occurrence and repair of the most cytotoxic DNA lesions, double-strand breaks, in particular at actively transcribed chromatin or related to DNA replication.
    Keywords:  Chromatin; DNA damage; DNA repair; Double-strand break; Genome instability
    DOI:  https://doi.org/10.1016/j.dnarep.2021.103210
  6. DNA Repair (Amst). 2021 Aug 08. pii: S1568-7864(21)00161-0. [Epub ahead of print]107 103205
    Role of histone acetyltransferases MOF and Tip60 in genome stability.
    Ulfat Syed Mir, Audesh Bhat, Arjamand Mushtaq, Shruti Pandita, Mohammad Altaf, Tej K Pandita.
      The accurate repair of DNA damage specifically the chromosomal double-strand breaks (DSBs) arising from exposure to physical or chemical agents, such as ionizing radiation (IR) and radiomimetic drugs is critical in maintaining genomic integrity. The DNA DSB response and repair is facilitated by hierarchical signaling networks that orchestrate chromatin structural changes specifically histone modifications which impact cell-cycle checkpoints through enzymatic activities to repair the broken DNA ends. Various histone posttranslational modifications such as phosphorylation, acetylation, methylation and ubiquitylation have been shown to play a role in DNA damage repair. Recent studies have provided important insights into the role of histone-specific modifications in sensing DNA damage and facilitating the DNA repair. Histone modifications have been shown to determine the pathway choice for repair of DNA DSBs. This review will summarize the role of important histone acetyltransferases MOF and Tip60 mediated acetylation in repair of DNA DSBs in eukaryotic cells.
    Keywords:  DNA DSB repair; Histone acetylation; Histone acetyltransferases; MOF; TIP60
    DOI:  https://doi.org/10.1016/j.dnarep.2021.103205
  7. DNA Repair (Amst). 2021 Aug 03. pii: S1568-7864(21)00155-5. [Epub ahead of print]107 103199
    Toxic R-loops: Cause or consequence of replication stress?
    Samira Kemiha, Jérôme Poli, Yea-Lih Lin, Armelle Lengronne, Philippe Pasero.
      Transcription-replication conflicts (TRCs) represent a potential source of endogenous replication stress (RS) and genomic instability in eukaryotic cells but the mechanisms that underlie this instability remain poorly understood. Part of the problem could come from non-B DNA structures called R-loops, which are formed of a RNA:DNA hybrid and a displaced ssDNA loop. In this review, we discuss different scenarios in which R-loops directly or indirectly interfere with DNA replication. We also present other types of TRCs that may not depend on R-loops to impede fork progression. Finally, we discuss alternative models in which toxic RNA:DNA hybrids form at stalled forks as a consequence - but not a cause - of replication stress and interfere with replication resumption.
    Keywords:  Genomic instability; R-loops; RNA:DNA hybrids; Replication; Transcription
    DOI:  https://doi.org/10.1016/j.dnarep.2021.103199
  8. FEBS J. 2021 Aug 17.
    G-quadruplexes in the mitochondrial genome - a cause for instability.
    Sneha Sarkar, Mridula Nambiar.
      Accumulation of mutations such as deletions in mitochondrial DNA is associated with ageing, cancer and human genetic disorders. These deletions are often flanked by GC-skewed sequence motifs that can potentially fold into secondary non-B DNA conformations. G-quadruplexes are emerging as key initiators of mitochondrial genomic instability. In this issue, Dahal et al provide an in silico analysis of sequence motifs that can fold into altered DNA structures in mitochondrial genomic regions that contain frequent deletions. They show the formation of five G-quadruplexes near such frequent breakpoints using biochemical and biophysical approaches in vitro and more importantly inside mammalian cells. Comment on: https://doi.org/10.1111/febs.16113.
    Keywords:  G4; Non-B DNA; genomic instability; mitochondrial DNA deletions
    DOI:  https://doi.org/10.1111/febs.16149
This page is being maintained by Thomas Krichel. It was last updated on 2021‒08‒22 at 18:10:44.