Review ArticleEntrenching role of cell cycle checkpoints and autophagy for maintenance of genomic integrity
Introduction
The genome of a cell is comprised of the genetic material (including DNA/RNA/epigenetic determinants and pertinent developmental gene expression) which is meant to be conveyed securely to the future generations. During the course of DNA replication, oxidative DNA lesions and chromatid breaks occur which get accumulated in eukaryotic cells [1,2]. DNA repair and the DNA damage response are essential not only for the normal progression of basic processes of transcription and replication but also for maintaining genomic stability and avoiding the development of neurodegenerative and immunodeficiency diseases, malignancies, etc. [3,4]. Under normal conditions, an appropriate synchronization of DNA damage sensing and activation of appropriate DNA damage repair machinery minimizes the somatic alteration in the genome [[5], [6], [7]]. Hereditary syndromes such as Lynch syndrome, breast, and ovarian cancer result from germline defects in mismatch repair pathway and homologous recombination respectively, which highlight the importance of genomic integrity against genotoxic insults [8,9].
Cell cycle regulates the crucial phenomena of cell division and growth of the individual as it is dynamically monitored at different phases called as ‘cell cycle checkpoints’. These checkpoints monitor the successful completion of the previous phase and decide whether the cell should proceed to the next phase of the cell cycle or take a halt or quit [10]. Under genotoxic stress conditions, alteration/damage in DNA strands of the cell results into cell cycle arrest and leads to the activation of diverse DNA damage repair pathways which are regulated by several specialized proteins [11,12]. Ataxia-telangiectasia mutated (ATM), ATM and RAD3-related (ATR) and p53 are the key cell cycle checkpoints regulatory proteins which contribute to the cell cycle arrest/apoptosis or progression of the cell cycle [13,14].
Autophagy is one of the cell surveillance processes over DNA damage response (DDR) which plays a vital role in cell survival. Autophagy is precisely described as a catabolic pathway which gets activated under the nutrient-deprived conditions in the cell [15]. In recent years, numerous studies suggest that autophagy plays a vital role in various tumor suppressor pathways [16]. Dysfunctional autophagy or autophagy-deficiency predisposes a cell towards enhanced DNA damage and instability of chromosome [17]. Cancer research has revealed that autophagy works as a barrier in malignant transformation as it preserves intracellular homeostasis of the cell. The precise molecular mechanism by which autophagy suppresses this tumor progression remains to be unearthed. In this review, the focus is on the prominence of genomic integrity, DNA damage, response to DNA damage by repair pathways and how these are regulated by cell cycle and cell cycle checkpoints. We also attempt to address the intricate interactions between autophagy in DDR and cell cycle regulation.
Section snippets
Prerequisite of Genomic integrity maintenance against DNA damaging events
Discovery of DNA (in 1953) brought in a revolution and transformed the thought process of the whole scientific world. DNA is a principal player which is used to express and faithfully transfer genetic information from one generation to another. The unearthing of DNA (structure and function) helped scientists to understand how DNA accomplishes itself to synchronize the whole cellular and metabolic activities of the cell at the molecular level. As DNA is known to have coding sequences which are
DNA damage reaponse (DDR)
The cells have evolved a highly orchestrated mechanism to combat the numerous DNA assaults, generally named the DNA damage response (DDR). DNA damage responses are a regimented series of diverse steps activated by discrete specific pathways. During stress conditions, prevalence of DNA lesions trigger an array of processes which include (1) sensing of DNA damage, repair or removal of DNA damage to restore the integrity of the genome; (2) cell cycle checkpoints activation which renders cell for
Recognition of DNA damage, recruitment of DNA repair machinery and commencement of repair process
Cells have different biochemical pathways to restore altered genomic integrity and preserve cellular homeostasis (Fig. 2). In fact, cells have developed a diverse set of machineries for detection and repair of various types of DNA damage. The repair of specific DNA lesion is carried out by specific pathway thus, making the list of of repair pathways long.
DNA damage-induced cell cycle checkpoints
DSBs provokes DNA damage response (DDR) activation, which reversibly impedes cell cycle progress to permit time for DNA repair. Once the DNA is repaired successfully, the cell recommences the cell cycle by switching off the DDR [62]. Cdks (Cyclin-dependent kinases) control transitions of the cell cycle as they depend and necessitate cyclin binding for its activity and substrate selectivity [63]. The DDR elicit cell cycle arrest in G1 or G2 phase or can retard S-phase replication but it does not
Autophagy: a critical regulator of cellular homeostasis
Autophagy is highly conserved in all eukaryotes, preserving cellular homeostasis in stress conditions like nutrient deprivation, oxidative stress and DNA damage [[92], [93], [94]]. Malfunction in autophagy leads to neurodegenerative disorders in mammalian models including Huntington disease (Huntingtin’s (HTT) accumulation), Alzheimer’s disease (amyloid-β (Aβ) and Tau accumulation) and Parkinson’s disease (α-synuclein accumulation) [95]. Dysregulated autophagy is also involved in the metabolic
Adaptation and Recovery of cell cycle and autophagy upon DNA damage
Double-strand breaks, if remain unrepaired, cause the halt of the cell cycle but eventually, the cell escapes from this growth inhibitory phase i.e. cell cycle arrest by a process known as ‘adaptation’ [109]. Studies have shown that cells might be arrested before the adaptation process which is around 12−15 h (time equivalent to 5–6 normal cell cycle) [110]. During the persistence of intense DNA damage, adaptation is accompanied by several factors which play key roles like loss of
Important proteins in DDR signaling mediated autophagy induction
The interaction of autophagy with DNA damage and their co-ordinated mechanisms are being studied with full vigor, as this mechanistic cellular work was also awarded Nobel Prize in the area of Physiology and Medicine in 2016 and Chemistry in 2015 [[135], [136], [137]]. Autophagy becomes a survival mechanism for the cell at a minimal level of DNA damage while at higher levels the balance is shifted towards death. Oxidative and nitrosative stress-induced DSBs activates ATM which then activates
Mitochondrial DNA damage and mitophagy induction
Mammalian mitochondria contain multiple small genomes which are also under the threat of continuous genotoxic insults. Progressive damage to mitochondrial DNA (mtDNA) is considered to be the underlying cause of various diseases [162,163]. Many DNA repair systems that work on nuclear DNA damage are not active in mitochondria. Depending upon the magnitude and type of damage, mitochondrial DNA destruction is triggered either directly or through specific forms of autophagy, like mitophagy.
Summary and future perspectives
Genomic integrity and its maintenance are crucial for the maintenance of cellular homeostasis. Exposure to the physical and chemical genotoxic agents leads to the production of DNA lesions which might culminate into the generation of mutations and chromosomal aberrations. To limit the harmful effects of modulation in the genomic stability, cell cycle checkpoints gets activated which stimulate the cell to respond by activation of DNA damage repair pathways and renders cell appropriate time for
Funding source
All sources of funding should also be acknowledged and you should declare any involvement of study sponsors in the study design; collection, analysis and interpretation of data; the writing of the manuscript; the decision to submit the manuscript for publication. If the study sponsors had no such involvement, this should be stated.
Author contributions
SKA and AS conceived the original idea and contributed majorly in collecting and organizing information. Manuscript compilation and images were created jointly by SKA, AS and NS. PK designed the framework of review and gave insights in compilation and editing of the review paper. All authors have discussed and contributed to the final manuscript.
Declaration of Competing Interest
The authors declare no potential conflict of interest regarding authorship and publication of this manuscript.
Acknowledgments
This work was supported by grants provided by CSIR, Project HCP‐0019 to PK, DBT-Senior Research Fellowship to SKA, DST-INSPIRE-Senior Research Fellowship to AS, and UGC-Junior Research Fellowship to NS. The authors are grateful to institutional manuscript review committee for providing manuscript communication number 3605 for this manuscript.
References (174)
- et al.
Removal of oxidatively generated DNA damage by overlapping repair pathways
Free Radic. Biol. Med.
(2017) - et al.
Coupling of homologous recombination and the checkpoint by ATR
Mol. Cell
(2017) - et al.
DNA protein crosslink proteolysis repair: from yeast to premature ageing and cancer in humans
DNA Repair (Amst.)
(2018) - et al.
Is DNA damage indispensable for stress-induced senescence?
Mech. Ageing Dev.
(2018) - et al.
Deployment of DNA polymerases beta and lambda in single-nucleotide and multinucleotide pathways of mammalian base excision DNA repair
DNA Repair (Amst.)
(2019) - et al.
Base excision repair and nucleotide excision repair
Genome Stability
(2016) - et al.
Tripartite DNA lesion recognition and verification by XPC, TFIIH, and XPA in nucleotide excision repair
Mol. Cell
(2015) Nucleotide excision repair in humans
DNA Repair (Amst.)
(2015)- et al.
The Ku heterodimer: function in DNA repair and beyond
Mutat. Res. Mutat. Res.
(2015) - et al.
Mammalian RAD52 functions in break-induced replication repair of collapsed DNA replication forks
Mol. Cell
(2016)
The prognostic value of HOXA13 in solid tumors: a meta-analysis
Clin. Chim. Acta
The binding of Ku antigen to homeodomain proteins promotes their phosphorylation by DNA-dependent protein kinase
J. Biol. Chem.
Distinct mechanisms for opposite functions of homeoproteins Cdx2 and HoxB7 in double-strand break DNA repair in colon cancer cells
Cancer Lett.
Tudor: a versatile family of histone methylation ‘readersâ€TM
Trends Biochem. Sci.
DNA damage during mitosis in human cells delays the metaphase/anaphase transition via the spindle-assembly checkpoint
Curr. Biol.
Inactive Atm abrogates DSB repair in mouse cerebellum more than does Atm loss, without causing a neurological phenotype
DNA Repair (Amst.)
p53-deficient cells rely on ATM- and ATR-mediated checkpoint signaling through the p38MAPK/MK2 pathway for survival after DNA damage
Cancer Cell
Differential contribution of inhibitory phosphorylation of CDC2 and CDK2 for unperturbed cell cycle control and DNA integrity checkpoints
J. Biol. Chem.
Chk1 and Wee1 control genotoxic-stress induced G2–M arrest in melanoma cells
Cell. Signal.
G2-checkpoint targeting and radiosensitization of HPV/p16-positive HNSCC cells through the inhibition of Chk1 and Wee1
Radiother. Oncol.
SCFbetaTrCP-mediated degradation of Claspin regulates recovery from the DNA replication checkpoint response
Mol. Cell
Polo-like kinase-1 controls proteasome-dependent degradation of Claspin during checkpoint recovery
Curr. Biol.
Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks
Mol. Cell
Autophagy and the integrated stress response
Mol. Cell
Autophagy and neurodegeneration: pathogenic mechanisms and therapeutic opportunities
Neuron
Autophagy: renovation of cells and tissues
Cell
Methods in mammalian autophagy research
Cell
DNA repair diseases: What do they tell us about cancer and aging?
Genet. Mol. Biol.
A history of the DNA repair and mutagenesis field: the discovery of base excision repair
DNA Repair (Amst)
DNA damage response pathways and cancer
Abeloff’s Clinical Oncology
Autophagy in cell death: an innocent convict?
J. Clin. Invest.
Molecular biology: the expanding arena of DNA repair
Nature
DNA repair, genome stability and cancer: a historical perspective
Nat. Rev. Cancer
DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis
Nature
DNA damage response and repair in ovarian cancer: potential targets for therapeutic strategies
DNA Repair (Amst.)
Orchestration of DNA damage checkpoint dynamics across the human cell cycle
Cell Syst.
Cell cycle checkpoint in cancer: a therapeutically targetable double-edged sword
J. Exp. Clin. Cancer Res.
DNA damage sensing by the ATM and ATR kinases
Cold Spring Harb. Perspect. Biol.
Cell cycle arrest through indirect transcriptional repression by p53: I have a DREAM
Cell Death Differ.
Inhibition of autophagy in hepatocarcinoma cells promotes chemotherapeutic agent-induced apoptosis during nutrient deprivation
Oncol. Rep.
The autophagic network and cancer
Nat. Cell Biol.
The interplay between autophagy and tumorigenesis: exploiting autophagy as a means of anticancer therapy
Biol. Rev.
Dancing with the DNA damage response: next-generation anti-cancer therapeutic strategies
Ther. Adv. Med. Oncol.
The human gut bacterial genotoxin colibactin alkylates DNA
Science
DNA damage and the balance between survival and death in cancer biology
Nat. Rev. Cancer
Mechanisms of DNA damage, repair, and mutagenesis
Environ. Mol. Mutagen.
ROS and the DNA damage response in cancer
Redox Biol.
Impact of infrared radiation on UVB-induced skin tumourigenesis in wild type C57BL/6 mice
Photochem. Photobiol. Sci.
Quantifying cigarette smoke induced oxidative DNA damage of wild type & XPC knockdown human bronchial cells using human 8-oxoguanine DNA glycosylase 1
Proceedings of IMPRS
The control of meiotic recombination in the human genome
Crit. Rev. Eukaryot. Gene Expr.
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Both the authors have contributed equally.