Regulation of Structure-Specific Endonucleases in Replication Stress

Replication stress results in various forms of aberrant replication intermediates that need to be resolved for faithful chromosome segregation. Structure-specific endonucleases (SSEs) recognize DNA secondary structures rather than primary sequences and play key roles during DNA repair and replication stress. Holliday junction resolvase MUS81 (methyl methane sulfonate (MMS), and UV-sensitive protein 81) and XPF (xeroderma pigmentosum group F-complementing protein) are a subset of SSEs that resolve aberrant replication structures. To ensure genome stability and prevent unnecessary DNA breakage, these SSEs are tightly regulated by the cell cycle and replication checkpoints. We discuss the regulatory network that control activities of MUS81 and XPF and briefly mention other SSEs involved in the resolution of replication intermediates.

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GCNA preserves genome integrity and fertility across species

10.1101/570804 ◽

2019 ◽

Author(s):

Varsha Bhargava ◽

Courtney D. Goldstein ◽

Logan Russell ◽

Lin Xu ◽

Murtaza Ahmed ◽

...

Keyword(s):

Germ Cell ◽

Chromosome Segregation ◽

Germ Cells ◽

Genome Stability ◽

Replication Stress ◽

Genome Integrity ◽

Intrinsically Disordered ◽

Early Embryos ◽

The Face ◽

Protein Crosslinks

SUMMARYThe propagation of species depends on the ability of germ cells to protect their genome in the face of numerous exogenous and endogenous threats. While these cells employ a number of known repair pathways, specialized mechanisms that ensure high-fidelity replication, chromosome segregation, and repair of germ cell genomes remain incompletely understood. Here, we identify Germ Cell Nuclear Acidic Peptidase (GCNA) as a highly conserved regulator of genome stability in flies, worms, zebrafish, and humans. GCNA contains a long acidic intrinsically disordered region (IDR) and a protease-like SprT domain. In addition to chromosomal instability and replication stress, GCNA mutants accumulate DNA-protein crosslinks (DPCs). GCNA acts in parallel with a second SprT domain protein Spartan. Structural analysis reveals that while the SprT domain is needed to limit meiotic and replicative damage, most of GCNA’s function maps to its IDR. This work shows GCNA protects germ cells from various sources of damage, providing novel insights into conserved mechanisms that promote genome integrity across generations.HighlightsGCNA ensures genomic stability in germ cells and early embryos across speciesGCNA limits replication stress and DNA double stranded breaksGCNA restricts DNA-Protein Crosslinks within germ cells and early embryosThe IDR and SprT domains of GCNA govern distinct aspects of genome integrityGraphic Abstract

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Histone H3G34R mutation causes replication stress, homologous recombination defects and genomic instability in S. pombe

eLife ◽

10.7554/elife.27406 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 13

Author(s):

Rajesh K Yadav ◽

Carolyn M Jablonowski ◽

Alfonso G Fernandez ◽

Brandon R Lowe ◽

Ryan A Henry ◽

...

Keyword(s):

Homologous Recombination ◽

Fission Yeast ◽

Genomic Instability ◽

Chromosome Segregation ◽

Replication Fork ◽

Replication Stress ◽

Damage Repair ◽

Replication Intermediates ◽

Insight Into

Recurrent somatic mutations of H3F3A in aggressive pediatric high-grade gliomas generate K27M or G34R/V mutant histone H3.3. H3.3-G34R/V mutants are common in tumors with mutations in p53 and ATRX, an H3.3-specific chromatin remodeler. To gain insight into the role of H3-G34R, we generated fission yeast that express only the mutant histone H3. H3-G34R specifically reduces H3K36 tri-methylation and H3K36 acetylation, and mutants show partial transcriptional overlap with set2 deletions. H3-G34R mutants exhibit genomic instability and increased replication stress, including slowed replication fork restart, although DNA replication checkpoints are functional. H3-G34R mutants are defective for DNA damage repair by homologous recombination (HR), and have altered HR protein dynamics in both damaged and untreated cells. These data suggest H3-G34R slows resolution of HR-mediated repair and that unresolved replication intermediates impair chromosome segregation. This analysis of H3-G34R mutant fission yeast provides mechanistic insight into how G34R mutation may promote genomic instability in glioma.

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Faculty Opinions recommendation of MUS81 nuclease activity is essential for replication stress tolerance and chromosome segregation in BRCA2-deficient cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727815151.793539951 ◽

2017 ◽

Author(s):

Mirit Aladjem ◽

Haiqing Fu

Keyword(s):

Stress Tolerance ◽

Chromosome Segregation ◽

Replication Stress ◽

Nuclease Activity

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Coordinated Degradation of Replisome Components Ensures Genome Stability upon Replication Stress in the Absence of the Replication Fork Protection Complex

PLoS Genetics ◽

10.1371/journal.pgen.1003213 ◽

2013 ◽

Vol 9 (1) ◽

pp. e1003213 ◽

Cited By ~ 19

Author(s):

Laura C. Roseaulin ◽

Chiaki Noguchi ◽

Esteban Martinez ◽

Melissa A. Ziegler ◽

Takashi Toda ◽

...

Keyword(s):

Replication Fork ◽

Genome Stability ◽

Replication Stress ◽

Fork Protection Complex

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Detours to Replication: Functions of Specialized DNA Polymerases during Oncogene-induced Replication Stress

International Journal of Molecular Sciences ◽

10.3390/ijms19103255 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3255 ◽

Cited By ~ 6

Author(s):

Wei-Chung Tsao ◽

Kristin Eckert

Keyword(s):

Dna Replication ◽

Stress Responses ◽

Dna Polymerases ◽

Repetitive Sequences ◽

Replication Stress ◽

Fragile Sites ◽

Cancer Development ◽

Cycle Arrest ◽

Chromosomal Fragile Sites ◽

Dna Secondary Structures

Incomplete and low-fidelity genome duplication contribute to genomic instability and cancer development. Difficult-to-Replicate Sequences, or DiToRS, are natural impediments in the genome that require specialized DNA polymerases and repair pathways to complete and maintain faithful DNA synthesis. DiToRS include non B-DNA secondary structures formed by repetitive sequences, for example within chromosomal fragile sites and telomeres, which inhibit DNA replication under endogenous stress conditions. Oncogene activation alters DNA replication dynamics and creates oncogenic replication stress, resulting in persistent activation of the DNA damage and replication stress responses, cell cycle arrest, and cell death. The response to oncogenic replication stress is highly complex and must be tightly regulated to prevent mutations and tumorigenesis. In this review, we summarize types of known DiToRS and the experimental evidence supporting replication inhibition, with a focus on the specialized DNA polymerases utilized to cope with these obstacles. In addition, we discuss different causes of oncogenic replication stress and its impact on DiToRS stability. We highlight recent findings regarding the regulation of DNA polymerases during oncogenic replication stress and the implications for cancer development.

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Heterochromatin: Guardian of the Genome

Annual Review of Cell and Developmental Biology ◽

10.1146/annurev-cellbio-100617-062653 ◽

2018 ◽

Vol 34 (1) ◽

pp. 265-288 ◽

Cited By ~ 100

Author(s):

Aniek Janssen ◽

Serafin U. Colmenares ◽

Gary H. Karpen

Keyword(s):

Chromosome Segregation ◽

Genome Stability ◽

Constitutive Heterochromatin ◽

Repetitive Sequences ◽

Genome Integrity ◽

Chromatin Domain ◽

Cellular Processes ◽

Eukaryotic Nucleus ◽

And Function ◽

Heterochromatin Structure

Constitutive heterochromatin is a major component of the eukaryotic nucleus and is essential for the maintenance of genome stability. Highly concentrated at pericentromeric and telomeric domains, heterochromatin is riddled with repetitive sequences and has evolved specific ways to compartmentalize, silence, and repair repeats. The delicate balance between heterochromatin epigenetic maintenance and cellular processes such as mitosis and DNA repair and replication reveals a highly dynamic and plastic chromatin domain that can be perturbed by multiple mechanisms, with far-reaching consequences for genome integrity. Indeed, heterochromatin dysfunction provokes genetic turmoil by inducing aberrant repeat repair, chromosome segregation errors, transposon activation, and replication stress and is strongly implicated in aging and tumorigenesis. Here, we summarize the general principles of heterochromatin structure and function, discuss the importance of its maintenance for genome integrity, and propose that more comprehensive analyses of heterochromatin roles in tumorigenesis will be integral to future innovations in cancer treatment.

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Parental exposure to methyl methane sulfonate of three-spined stickleback: contribution of DNA damage in male and female germ cells to further development impairment in progeny

Ecotoxicology ◽

10.1007/s10646-013-1088-3 ◽

2013 ◽

Vol 22 (5) ◽

pp. 815-824 ◽

Cited By ~ 15

Author(s):

R. Santos ◽

M. Palos-Ladeiro ◽

A. Besnard ◽

J. Reggio ◽

E. Vulliet ◽

...

Keyword(s):

Dna Damage ◽

Germ Cells ◽

Methyl Methane Sulfonate ◽

Methane Sulfonate ◽

Male And Female ◽

Parental Exposure ◽

Further Development

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Structure-Specific Endonucleases and the Resolution of Chromosome Underreplication

Genes ◽

10.3390/genes10030232 ◽

2019 ◽

Vol 10 (3) ◽

pp. 232 ◽

Cited By ~ 10

Author(s):

Benoît Falquet ◽

Ulrich Rass

Keyword(s):

Sister Chromatid ◽

Replication Fork ◽

Genome Stability ◽

Molecular Mechanisms ◽

Chromosome Breakage ◽

Repair Synthesis ◽

Daughter Cells ◽

Oncogene Activation ◽

Dna Repair Synthesis ◽

Replication Intermediates

Complete genome duplication in every cell cycle is fundamental for genome stability and cell survival. However, chromosome replication is frequently challenged by obstacles that impede DNA replication fork (RF) progression, which subsequently causes replication stress (RS). Cells have evolved pathways of RF protection and restart that mitigate the consequences of RS and promote the completion of DNA synthesis prior to mitotic chromosome segregation. If there is entry into mitosis with underreplicated chromosomes, this results in sister-chromatid entanglements, chromosome breakage and rearrangements and aneuploidy in daughter cells. Here, we focus on the resolution of persistent replication intermediates by the structure-specific endonucleases (SSEs) MUS81, SLX1-SLX4 and GEN1. Their actions and a recently discovered pathway of mitotic DNA repair synthesis have emerged as important facilitators of replication completion and sister chromatid detachment in mitosis. As RS is induced by oncogene activation and is a common feature of cancer cells, any advances in our understanding of the molecular mechanisms related to chromosome underreplication have important biomedical implications.

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