Elsevier

DNA Repair

Volume 86, February 2020, 102748
DNA Repair

Review Article
Entrenching role of cell cycle checkpoints and autophagy for maintenance of genomic integrity

https://doi.org/10.1016/j.dnarep.2019.102748Get rights and content

Abstract

Genomic integrity of the cell is crucial for the successful transmission of genetic information to the offspring and its survival. Persistent DNA damage induced by endogenous and exogenous agents leads to various metabolic manifestations. To combat this, eukaryotes have developed complex DNA damage response (DDR) pathway which senses the DNA damage and activates an arsenal of enzymes for the repair of damaged DNA. The active pathways for DNA repair are nucleotide excision repair (NER), base excision repair (BER) and mismatch repair (MMR) for single-strand break repair whereas homologous recombination (HR) and non-homologous end-joining (NHEJ) for double-strand break repair. OGG1 is a DNA glycosylase which initiates BER while Mre11-Rad50-Nbs1 (MRN) protein complex is the primary responder to DSBs which gets localized to damage sites. DNA damage response is meticulously executed by three related kinases: ATM, ATR, and DNA-PK. ATM- and ATR-dependent phosphorylation of p53, Chk1, and Chk2 regulate the G1/S, intra-S, or G2/M checkpoints of the cell cycle, respectively. Autophagy is an evolutionarily conserved process that plays a pivotal role in the regulation of DNA repair and maintains the cellular homeostasis. Genotoxic stress-induced altered autophagy occurs in a P53 dependent manner which is also the master regulator of genotoxic stress. A plethora of proteins involved in autophagy is regulated by p53 which involve DRAM, DAPK, and AMPK. As evident, the mtDNA is more prone to damage than nuclear DNA because of its close proximity to the site of ROS generation. Depending on the extent of damage either the repair mechanism or mitophagy gets triggered. SIRT1 is the master regulator which directs the stress response to mitophagy. Nix, a LC3 adapter also participates in Parkin mediated mitophagy. This review highlights the intricate crosstalks between DNA damage and cell cycle checkpoints activation. The DNA damage mediated regulation of autophagy and mitophagy is also reviewed in detail.

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.

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