Cell cycle checkpoints and DNA repair preserve the stability of the human genome

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.

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Chromosomal Instability Is Associated with Higher Expression of Genes Implicated in Epithelial-Mesenchymal Transition, Cancer Invasiveness, and Metastasis and with Lower Expression of Genes Involved in Cell Cycle Checkpoints, DNA Repair, and Chromatin Maintenance

Neoplasia ◽

10.1593/neo.08682 ◽

2008 ◽

Vol 10 (11) ◽

pp. 1222-IN26 ◽

Cited By ~ 25

Author(s):

Anna V. Roschke ◽

Oleg K. Glebov ◽

Samir Lababidi ◽

Kristen S. Gehlhaus ◽

John N. Weinstein ◽

...

Keyword(s):

Cell Cycle ◽

Dna Repair ◽

Chromosomal Instability ◽

Epithelial Mesenchymal Transition ◽

Cell Cycle Checkpoints ◽

Mesenchymal Transition ◽

Expression Of Genes ◽

Cancer Invasiveness ◽

Lower Expression

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Focus-ING on DNA Integrity: Implication of ING Proteins in Cell Cycle Regulation and DNA Repair Modulation

Cancers ◽

10.3390/cancers12010058 ◽

2019 ◽

Vol 12 (1) ◽

pp. 58

Author(s):

Jérôme Archambeau ◽

Alice Blondel ◽

Rémy Pedeux

Keyword(s):

Cell Cycle ◽

Dna Repair ◽

Chromatin Remodeling ◽

Tumor Suppressor Genes ◽

Cell Cycle Regulation ◽

Genomic Stability ◽

Dna Integrity ◽

Damage Response ◽

The Stability ◽

Cycle Regulation

The ING family of tumor suppressor genes is composed of five members (ING1-5) involved in cell cycle regulation, DNA damage response, apoptosis and senescence. All ING proteins belong to various HAT or HDAC complexes and participate in chromatin remodeling that is essential for genomic stability and signaling pathways. The gatekeeper functions of the INGs are well described by their role in the negative regulation of the cell cycle, notably by modulating the stability of p53 or the p300 HAT activity. However, the caretaker functions are described only for ING1, ING2 and ING3. This is due to their involvement in DNA repair such as ING1 that participates not only in NERs after UV-induced damage, but also in DSB repair in which ING2 and ING3 are required for accumulation of ATM, 53BP1 and BRCA1 near the lesion and for the subsequent repair. This review summarizes evidence of the critical roles of ING proteins in cell cycle regulation and DNA repair to maintain genomic stability.

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0801585105 ◽

2008 ◽

Vol 105 (46) ◽

pp. 17896-17901 ◽

Cited By ~ 60

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.

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

International Journal of Molecular Sciences ◽

10.3390/ijms20010074 ◽

2018 ◽

Vol 20 (1) ◽

pp. 74 ◽

Cited By ~ 10

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.

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