Transcription-coupled repair and mismatch repair contribute towards preserving genome integrity at mononucleotide repeat tracts

Mapping Intimacies ◽

10.1101/584342 ◽

2019 ◽

Cited By ~ 1

Author(s):

Ilias Georgakopoulos-Soares ◽

Gene Koh ◽

Josef Jiricny ◽

Martin Hemberg ◽

Serena Nik-Zainal

Keyword(s):

Mismatch Repair ◽

Analytical Approach ◽

Excision Repair ◽

Strand Break ◽

Genome Integrity ◽

Mononucleotide Repeat ◽

Physiological Conditions ◽

Strand Asymmetry ◽

Nucleotide Excision ◽

Reference Human Genome

Introductory paragraphThe mechanisms that underpin how insertions or deletions (indels) become fixed in DNA have primarily been ascribed to replication-related and/or double-strand break (DSB)-related processes. We introduce a novel way to evaluate indels, orientating them relative to gene transcription. In so doing, we reveal a number of surprising findings: First, there is a transcriptional strand asymmetry in the distribution of mononucleotide repeat tracts in the reference human genome. Second, there is a strong transcriptional strand asymmetry of indels across 2,575 whole genome sequenced human cancers. We suggest that this is due to the activity of transcription-coupled nucleotide excision repair (TC-NER). Furthermore, TC-NER interacts with mismatch repair (MMR) under physiological conditions to produce strand bias. Finally, we show how insertions and deletions differ in their dependencies on these repair pathways. Our novel analytical approach reveals new insights into the contribution of DNA repair towards indel mutagenesis in human cells.

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Removal of One Nonhomologous DNA End During Gene Conversion by a RAD1- and MSH2-Independent Pathway

Genetics ◽

10.1093/genetics/151.4.1409 ◽

1999 ◽

Vol 151 (4) ◽

pp. 1409-1423 ◽

Cited By ~ 6

Author(s):

Mónica P Colaiácovo ◽

Frédéric Pâques ◽

James E Haber

Keyword(s):

Saccharomyces Cerevisiae ◽

Homologous Recombination ◽

Gene Conversion ◽

Mismatch Repair ◽

Excision Repair ◽

Strand Break ◽

Template Sequence ◽

New Synthesis ◽

Nucleotide Excision ◽

Strand Annealing

Abstract Repair of a double-strand break (DSB) by homologous recombination depends on the invasion of a 3′-ended strand into an intact template sequence to initiate new DNA synthesis. When the end of the invading DNA is not homologous to the donor, the nonhomologous sequences must be removed before new synthesis can begin. In Saccharomyces cerevisiae, the removal of these ends depends on both the nucleotide excision repair endonuclease Rad1p/Rad10p and the mismatch repair proteins Msh2p/Msh3p. In rad1 or msh2 mutants, when both ends of the DSB have nonhomologous ends, repair is reduced ∼90-fold compared to a plasmid with perfect ends; however, with only one nonhomologous end, repair is reduced on average only 5-fold. These results suggest that yeast has an alternative, but less efficient, way to remove a nonhomologous tail from the second end participating in gene conversion. When the removal of one nonhomologous end is impaired in rad1 and msh2 mutants, there is also a 1-hr delay in the appearance of crossover products of gene conversion, compared to noncrossovers. We interpret these results in terms of the formation and resolution of alternative intermediates of a synthesis-dependent strand annealing mechanism.

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A Mutation in a Saccharomyces cerevisiae Gene (RAD3) Required for Nucleotide Excision Repair and Transcription Increases the Efficiency of Mismatch Correction

Genetics ◽

10.1093/genetics/144.2.459 ◽

1996 ◽

Vol 144 (2) ◽

pp. 459-466 ◽

Cited By ~ 1

Author(s):

Yingying Yang ◽

Anthony L Johnson ◽

Leland H Johnston ◽

Wolfram Siede ◽

Errol C Friedberg ◽

...

Keyword(s):

Saccharomyces Cerevisiae ◽

Mismatch Repair ◽

Excision Repair ◽

Spontaneous Mutation ◽

Surprising Result ◽

Spontaneous Mutation Rate ◽

Mismatch Correction ◽

Nucleotide Excision ◽

Repair Genes ◽

Type Strains

Abstract RAD3 functions in DNA repair and transcription in Saccharomyces cerevisiae and particular rad3 alleles confer a mutator phenotype, possibly as a consequence of defective mismatch correction. We assessed the potential involvement of the Rad3 protein in mismatch correction by comparing heteroduplex repair in isogenic rad3-1 and wild-type strains. The rad3-1 allele increased the spontaneous mutation rate but did not prevent heteroduplex repair or bias its directionality. Instead, the efficiency of mismatch correction was enhanced in the rad3-1 strain. This surprising result prompted us to examine expression of yeast mismatch repair genes. We determined that MSH2, but not MLH1, is transcriptionally regulated during the cell-cycle like PMSl, and that rad3-1 does not increase the transcript levels for these genes in log phase cells. These observations suggest that the rad3-1 mutation gives rise to an enhanced efficiency of mismatch correction via a process that does not involve transcriptional regulation of mismatch repair. Interestingly, mismatch repair also was more efficient when error-editing by yeast DNA polymerase δ was eliminated. We discuss our results in relation to possible mechanisms that may link the rad3-1 mutation to mismatch correction efficiency.

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Learning mutational signatures and their multidimensional genomic properties with TensorSignatures

Nature Communications ◽

10.1038/s41467-021-23551-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Harald Vöhringer ◽

Arne Van Hoeck ◽

Edwin Cuppen ◽

Moritz Gerstung

Keyword(s):

Somatic Hypermutation ◽

Excision Repair ◽

Metastatic Cancer ◽

Strand Break ◽

Lymphoid Leukaemia ◽

Mutational Signatures ◽

Transcription Start Sites ◽

Nucleotide Excision ◽

Cancer Types ◽

Underlying Processes

AbstractWe present TensorSignatures, an algorithm to learn mutational signatures jointly across different variant categories and their genomic localisation and properties. The analysis of 2778 primary and 3824 metastatic cancer genomes of the PCAWG consortium and the HMF cohort shows that all signatures operate dynamically in response to genomic states. The analysis pins differential spectra of UV mutagenesis found in active and inactive chromatin to global genome nucleotide excision repair. TensorSignatures accurately characterises transcription-associated mutagenesis in 7 different cancer types. The algorithm also extracts distinct signatures of replication- and double strand break repair-driven mutagenesis by APOBEC3A and 3B with differential numbers and length of mutation clusters. Finally, TensorSignatures reproduces a signature of somatic hypermutation generating highly clustered variants at transcription start sites of active genes in lymphoid leukaemia, distinct from a general and less clustered signature of Polη-driven translesion synthesis found in a broad range of cancer types. In summary, TensorSignatures elucidates complex mutational footprints by characterising their underlying processes with respect to a multitude of genomic variables.

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Regulation of Mitotic Homeologous Recombination in Yeast: Functions of Mismatch Repair and Nucleotide Excision Repair Genes

Genetics ◽

10.1093/genetics/154.1.133 ◽

2000 ◽

Vol 154 (1) ◽

pp. 133-146 ◽

Cited By ~ 1

Author(s):

Ainsley Nicholson ◽

Miyono Hendrix ◽

Sue Jinks-Robertson ◽

Gray F Crouse

Keyword(s):

Saccharomyces Cerevisiae ◽

Mismatch Repair ◽

Nucleotide Excision Repair ◽

Excision Repair ◽

Mitotic Recombination ◽

Inverted Repeats ◽

Replication Errors ◽

Nucleotide Excision ◽

Homeologous Recombination ◽

Repair Genes

Abstract The Saccharomyces cerevisiae homologs of the bacterial mismatch repair proteins MutS and MutL correct replication errors and prevent recombination between homeologous (nonidentical) sequences. Previously, we demonstrated that Msh2p, Msh3p, and Pms1p regulate recombination between 91% identical inverted repeats, and here use the same substrates to show that Mlh1p and Msh6p have important antirecombination roles. In addition, substrates containing defined types of mismatches (base-base mismatches; 1-, 4-, or 12-nt insertion/deletion loops; or 18-nt palindromes) were used to examine recognition of these mismatches in mitotic recombination intermediates. Msh2p was required for recognition of all types of mismatches, whereas Msh6p recognized only base-base mismatches and 1-nt insertion/deletion loops. Msh3p was involved in recognition of the palindrome and all loops, but also had an unexpected antirecombination role when the potential heteroduplex contained only base-base mismatches. In contrast to their similar antimutator roles, Pms1p consistently inhibited recombination to a lesser degree than did Msh2p. In addition to the yeast MutS and MutL homologs, the exonuclease Exo1p and the nucleotide excision repair proteins Rad1p and Rad10p were found to have roles in inhibiting recombination between mismatched substrates.

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Abasic Sites in the Transcribed Strand of Yeast DNA Are Removed by Transcription-Coupled Nucleotide Excision Repair

Molecular and Cellular Biology ◽

10.1128/mcb.00308-10 ◽

2010 ◽

Vol 30 (13) ◽

pp. 3206-3215 ◽

Cited By ~ 45

Author(s):

Nayun Kim ◽

Sue Jinks-Robertson

Keyword(s):

Nucleotide Excision Repair ◽

Excision Repair ◽

Genome Integrity ◽

Genetic Studies ◽

Abasic Sites ◽

Dna And Rna ◽

Nucleotide Excision ◽

Ap Sites ◽

Base Excision ◽

Ap Site

ABSTRACT Abasic (AP) sites are potent blocks to DNA and RNA polymerases, and their repair is essential for maintaining genome integrity. Although AP sites are efficiently dealt with through the base excision repair (BER) pathway, genetic studies suggest that repair also can occur via nucleotide excision repair (NER). The involvement of NER in AP-site removal has been puzzling, however, as this pathway is thought to target only bulky lesions. Here, we examine the repair of AP sites generated when uracil is removed from a highly transcribed gene in yeast. Because uracil is incorporated instead of thymine under these conditions, the position of the resulting AP site is known. Results demonstrate that only AP sites on the transcribed strand are efficient substrates for NER, suggesting the recruitment of the NER machinery by an AP-blocked RNA polymerase. Such transcription-coupled NER of AP sites may explain previously suggested links between the BER pathway and transcription.

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A Synthetic Interaction between CDC20 and RAD4 in Saccharomyces cerevisiae upon UV Irradiation

Molecular Biology International ◽

10.1155/2014/519290 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8

Author(s):

Bernadette Connors ◽

Lauren Rochelle ◽

Asela Roberts ◽

Graham Howard

Keyword(s):

Saccharomyces Cerevisiae ◽

Nucleotide Excision Repair ◽

Uv Irradiation ◽

Double Mutant ◽

Excision Repair ◽

Strand Break ◽

Anaphase Promoting Complex ◽

End Joining ◽

Ubiquitin Ligase Complex ◽

Nucleotide Excision

Regulation of DNA repair can be achieved through ubiquitin-mediated degradation of transiently induced proteins. In Saccharomyces cerevisiae, Rad4 is involved in damage recognition during nucleotide excision repair (NER) and, in conjunction with Rad23, recruits other proteins to the site of damage. We identified a synthetic interaction upon UV exposure between Rad4 and Cdc20, a protein that modulates the activity of the anaphase promoting complex (APC/C), a multisubunit E3 ubiquitin ligase complex. The moderately UV sensitive Δrad4 strain became highly sensitive when cdc20-1 was present, and was rescued by overexpression of CDC20. The double mutant is also deficient in elicting RNR3-lacZ transcription upon exposure to UV irradiation or 4-NQO compared with the Δrad4 single mutant. We demonstrate that the Δrad4/cdc20-1 double mutant is defective in double strand break repair by way of a plasmid end-joining assay, indicating that Rad4 acts to ensure that damaged DNA is repaired via a Cdc20-mediated mechanism. This study is the first to present evidence that Cdc20 may play a role in the degradation of proteins involved in nucleotide excision repair.

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Interaction between the mismatch repair and nucleotide excision repair pathways in the prevention of 5-azacytidine-induced CG-to-GC mutations in Escherichia coli

DNA Repair ◽

10.1016/j.dnarep.2008.11.015 ◽

2009 ◽

Vol 8 (3) ◽

pp. 354-359 ◽

Cited By ~ 11

Author(s):

Photini Pitsikas ◽

Yaroslava Y. Polosina ◽

Claire G. Cupples

Keyword(s):

Escherichia Coli ◽

Mismatch Repair ◽

Nucleotide Excision Repair ◽

Excision Repair ◽

Nucleotide Excision ◽

Repair Pathways

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Mismatch repair and nucleotide excision repair proteins cooperate in the recognition of DNA interstrand crosslinks

Nucleic Acids Research ◽

10.1093/nar/gkp399 ◽

2009 ◽

Vol 37 (13) ◽

pp. 4420-4429 ◽

Cited By ~ 55

Author(s):

Junhua Zhao ◽

Aklank Jain ◽

Ravi R. Iyer ◽

Paul L. Modrich ◽

Karen M. Vasquez

Keyword(s):

Mismatch Repair ◽

Nucleotide Excision Repair ◽

Excision Repair ◽

Interstrand Crosslinks ◽

Dna Interstrand Crosslinks ◽

Nucleotide Excision

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Emerging Roles of Post-Translational Modifications in Nucleotide Excision Repair

Cells ◽

10.3390/cells9061466 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1466 ◽

Cited By ~ 1

Author(s):

Barbara N. Borsos ◽

Hajnalka Majoros ◽

Tibor Pankotai

Keyword(s):

Nucleotide Excision Repair ◽

Ubiquitin Ligase ◽

Excision Repair ◽

Fine Tuning ◽

Genome Integrity ◽

Repair Pathway ◽

Cyclobutane Pyrimidine Dimers ◽

Post Translational Modifications ◽

Pyrimidine Dimers ◽

Nucleotide Excision

Nucleotide excision repair (NER) is a versatile DNA repair pathway which can be activated in response to a broad spectrum of UV-induced DNA damage, such as bulky adducts, including cyclobutane-pyrimidine dimers (CPDs) and 6–4 photoproducts (6–4PPs). Based on the genomic position of the lesion, two sub-pathways can be defined: (I) global genomic NER (GG-NER), involved in the ablation of damage throughout the whole genome regardless of the transcription activity of the damaged DNA locus, and (II) transcription-coupled NER (TC-NER), activated at DNA regions where RNAPII-mediated transcription takes place. These processes are tightly regulated by coordinated mechanisms, including post-translational modifications (PTMs). The fine-tuning modulation of the balance between the proteins, responsible for PTMs, is essential to maintain genome integrity and to prevent tumorigenesis. In this review, apart from the other substantial PTMs (SUMOylation, PARylation) related to NER, we principally focus on reversible ubiquitylation, which involves E3 ubiquitin ligase and deubiquitylase (DUB) enzymes responsible for the spatiotemporally precise regulation of NER.

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