scholarly journals Extensive loss of cell cycle and DNA repair genes in an ancient lineage of bipolar budding yeasts

2019 ◽  
Author(s):  
Jacob L. Steenwyk ◽  
Dana A. Opulente ◽  
Jacek Kominek ◽  
Xing-Xing Shen ◽  
Xiaofan Zhou ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Repair ◽  
Excision Repair ◽  
Gc Content ◽  
Cell Cycle Checkpoints ◽  
Pyrimidine Dimer ◽  
Genome Integrity ◽  
Checkpoint Pathway ◽  
Accelerated Evolution ◽  
Ancient Lineage

AbstractCell cycle checkpoints and DNA repair processes protect organisms from potentially lethal mutational damage. Compared to other budding yeasts in the subphylum Saccharomycotina, we noticed that a lineage in the genus Hanseniaspora exhibited very high evolutionary rates, low GC content, small genome sizes, and lower gene numbers. To better understand Hanseniaspora evolution, we analyzed 25 genomes, including 11 newly sequenced, representing 18 / 21 known species in the genus. Our phylogenomic analyses identify two Hanseniaspora lineages, the fast-evolving lineage (FEL), which began diversifying ∼87 million years ago (mya), and the slow-evolving lineage (SEL), which began diversifying ∼54 mya. Remarkably, both lineages lost genes associated with the cell cycle and genome integrity, but these losses were greater in the FEL. For example, all species lost the cell cycle regulator WHI5, and the FEL lost components of the spindle checkpoint pathway (e.g., MAD1, MAD2) and DNA damage checkpoint pathway (e.g., MEC3, RAD9). Similarly, both lineages lost genes involved in DNA repair pathways, including the DNA glycosylase gene MAG1, which is part of the base excision repair pathway, and the DNA photolyase gene PHR1, which is involved in pyrimidine dimer repair. Strikingly, the FEL lost 33 additional genes, including polymerases (i.e., POL4 and POL32) and telomere-associated genes (e.g., RIF1, RFA3, CDC13, PBP2). Echoing these losses, molecular evolutionary analyses reveal that, compared to the SEL, the FEL stem lineage underwent a burst of accelerated evolution, which resulted in greater mutational loads, homopolymer instabilities, and higher fractions of mutations associated with the common endogenously damaged base, 8-oxoguanine. We conclude that Hanseniaspora is an ancient lineage that has diversified and thrived, despite lacking many otherwise highly conserved cell cycle and genome integrity genes and pathways, and may represent a novel system for studying cellular life without them.

scholarly journals ATR kinase is required for global genomic nucleotide excision repair exclusively during S phase in human cells

2008 ◽  
Vol 105 (46) ◽  
pp. 17896-17901 ◽  
Author(s):  
Yannick Auclair ◽  
Raphael Rouget ◽  
El Bachir Affar ◽  
Elliot A. Drobetsky
Keyword(s):  
Cell Cycle ◽  
Dna Repair ◽  
Nucleotide Excision Repair ◽  
Excision Repair ◽  
Human Tumor ◽  
Chemotherapeutic Agents ◽  
S Phase ◽  
Cell Cycle Checkpoints ◽  
Lung Fibroblasts ◽  
Nucleotide Excision

Global-genomic nucleotide excision repair (GG-NER) is the only pathway available to humans for removal, from the genome overall, of highly genotoxic helix-distorting DNA adducts generated by many environmental mutagens and certain chemotherapeutic agents, e.g., UV-induced 6–4 photoproducts (6–4PPs) and cyclobutane pyrimidine dimers (CPDs). The ataxia telangiectasia and rad-3-related kinase (ATR) is rapidly activated in response to UV-induced replication stress and proceeds to phosphorylate a plethora of downstream effectors that modulate primarily cell cycle checkpoints but also apoptosis and DNA repair. To investigate whether this critical kinase might participate in the regulation of GG-NER, we developed a novel flow cytometry-based DNA repair assay that allows precise evaluation of GG-NER kinetics as a function of cell cycle. Remarkably, inhibition of ATR signaling in primary human lung fibroblasts by treatment with caffeine, or with siRNA specifically targeting ATR, resulted in total inhibition of 6–4PP removal during S phase, whereas cells repaired normally during either G0/G1 or G2/M. Similarly striking S-phase-specific defects in GG-NER of both 6–4PPs and CPDs were documented in ATR-deficient Seckel syndrome skin fibroblasts. Finally, among six diverse model human tumor strains investigated, three manifested complete abrogation of 6–4PP repair exclusively in S-phase populations. Our data reveal a highly novel role for ATR in the regulation of GG-NER uniquely during S phase of the cell cycle, and indicate that many human cancers may be characterized by a defect in this regulation.

scholarly journals Impact of hypoxia on DNA repair and genome integrity

Mutagenesis ◽  
2019 ◽  
Vol 35 (1) ◽  
pp. 61-68 ◽  
Author(s):  
Alanna R Kaplan ◽  
Peter M Glazer
Keyword(s):  
Dna Repair ◽  
Cancer Progression ◽  
Base Excision Repair ◽  
Mutation Frequency ◽  
Excision Repair ◽  
Tumour Microenvironment ◽  
Genome Integrity ◽  
Future Directions ◽  
Homology Directed Repair ◽  
Base Excision

Abstract Hypoxia is a hallmark of the tumour microenvironment with profound effects on tumour biology, influencing cancer progression, the development of metastasis and patient outcome. Hypoxia also contributes to genomic instability and mutation frequency by inhibiting DNA repair pathways. This review summarises the diverse mechanisms by which hypoxia affects DNA repair, including suppression of homology-directed repair, mismatch repair and base excision repair. We also discuss the effects of hypoxia mimetics and agents that induce hypoxia on DNA repair, and we highlight areas of potential clinical relevance as well as future directions.

scholarly journals Human Exonuclease 1 (EXO1) Regulatory Functions in DNA Replication with Putative Roles in Cancer

2018 ◽  
Vol 20 (1) ◽  
pp. 74 ◽  
Author(s):  
Guido Keijzers ◽  
Daniela Bakula ◽  
Michael Petr ◽  
Nils Madsen ◽  
Amanuel Teklu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Repair ◽  
Dna Replication ◽  
Replication Fork ◽  
Cellular Transformation ◽  
Cell Cycle Checkpoints ◽  
Replication Process ◽  
Exonuclease 1 ◽  
Repair Pathways ◽  
Regulatory Functions

Human exonuclease 1 (EXO1), a 5′→3′ exonuclease, contributes to the regulation of the cell cycle checkpoints, replication fork maintenance, and post replicative DNA repair pathways. These processes are required for the resolution of stalled or blocked DNA replication that can lead to replication stress and potential collapse of the replication fork. Failure to restart the DNA replication process can result in double-strand breaks, cell-cycle arrest, cell death, or cellular transformation. In this review, we summarize the involvement of EXO1 in the replication, DNA repair pathways, cell cycle checkpoints, and the link between EXO1 and cancer.

Nucleoside analogs as a radiosensitizer modulating DNA repair, cell cycle checkpoints, and apoptosis

2019 ◽  
Vol 39 (1-3) ◽  
pp. 439-452
Author(s):  
Hironobu Yasui ◽  
Daisuke Iizuka ◽  
Wakako Hiraoka ◽  
Mikinori Kuwabara ◽  
Akira Matsuda ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Repair ◽  
Nucleoside Analogs ◽  
Cell Cycle Checkpoints

scholarly journals Breaking down cell cycle checkpoints and DNA repair during antigen receptor gene assembly

Oncogene ◽  
2007 ◽  
Vol 26 (56) ◽  
pp. 7759-7764 ◽  
Author(s):  
E Callén ◽  
M C Nussenzweig ◽  
A Nussenzweig
Keyword(s):  
Cell Cycle ◽  
Dna Repair ◽  
Receptor Gene ◽  
Antigen Receptor ◽  
Cell Cycle Checkpoints ◽  
Gene Assembly

scholarly journals Doxorubicin and vincristine affect undifferentiated rat spermatogonia

Reproduction ◽  
2017 ◽  
Vol 153 (6) ◽  
pp. 725-735 ◽  
Author(s):  
Hermance Beaud ◽  
Ans van Pelt ◽  
Geraldine Delbes
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Dna Repair ◽  
Cell Cycle Arrest ◽  
Excision Repair ◽  
Alkylating Agents ◽  
Dna Breaks ◽  
Cycle Arrest ◽  
A Cell ◽  
The Impact

Anticancer drugs, such as alkylating agents, can affect male fertility by targeting the DNA of proliferative spermatogonial stem cells (SSC). Therefore, to reduce such side effects, other chemotherapeutics are used. However, less is known about their potential genotoxicity on SSC. Moreover, DNA repair mechanisms in SSC are poorly understood. To model treatments deprived of alkylating agents that are commonly used in cancer treatment, we tested the impact of exposure to doxorubicin and vincristine, alone or in combination (MIX), on a rat spermatogonial cell line with SSC characteristics (GC-6spg). Vincristine alone induced a cell cycle arrest and cell death without genotoxic impact. On the other hand, doxorubicin and the MIX induced a dose-dependent cell death. More importantly, doxorubicin and the MIX induced DNA breaks, measured by the COMET assay, at a non-cytotoxic dose. To elucidate which DNA repair pathway is activated in spermatogonia after exposure to doxorubicin, we screened the expression of 75 genes implicated in DNA repair. Interestingly, all were expressed constitutively in GC-6spg, suggesting great potential to respond to genotoxic stress. Doxorubicin treatments affected the expression of 16 genes (>1.5 fold change;P < 0.05) involved in cell cycle, base/nucleotide excision repair, homologous recombination and non-homologous end joining (NHEJ). The significant increase in CDKN1A and XRCC1 suggest a cell cycle arrest and implies an alternative NHEJ pathway in response to doxorubicin-induced DNA breaks. Together, our results support the idea that undifferentiated spermatogonia have the ability to respond to DNA injury from chemotherapeutic compounds and escape DNA break accumulation.

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