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Features of DNA Repair in the Early Stages of Mammalian Embryonic Development

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Features of DNA Repair in the Early Stages of Mammalian Embryonic Development G C A T T A C G G C A T genes Review Features of DNA Repair in the Early Stages of Mammalian Embryonic Development Evgenia V. Khokhlova 1,2, Zoia S. Fesenko 1, Julia V. Sopova 1,3 and Elena I. Leonova 1,4,* 1 Institute of Translational Biomedicine, St. Petersburg State University, 199034 St. Petersburg, Russia; [email protected] (E.V.K.); [email protected] (Z.S.F.); [email protected] (J.V.S.) 2 Institute of Cytology of the Russian Academy of Sciences, 194064 St. Petersburg, Russia 3 Laboratory of Amyloid Biology, St. Petersburg State University, 199034 St. Petersburg, Russia 4 Preclinical Research Center, University of Science and Technology, 1 Olympic Ave, 354340 Sochi, Russia * Correspondence: [email protected]; Tel.: +8-(999)-232-92-58 Received: 29 August 2020; Accepted: 25 September 2020; Published: 27 September 2020 Abstract: Cell repair machinery is responsible for protecting the genome from endogenous and exogenous effects that induce DNA damage. Mutations that occur in somatic cells lead to dysfunction in certain tissues or organs, while a violation of genomic integrity during the embryonic period often leads to death. A mammalian embryo’s ability to respond to damaged DNA and repair it, as well as its sensitivity to specific lesions, is still not well understood. In this review, we combine disparate data on repair processes in the early stages of preimplantation development in mammalian embryos. Keywords: DNA repair; BER (base excision repair); NER (nucleotide excision repair); MMR (mismatch repair); DSBR (double strand break repair); HR (homologous recombination); NHEJ (nonhomologous end joining); MHEJ (microhomologies end joining); oocyte; zygote; blastocyst 1. Introduction DNA repair during the early stages of embryonic development has one of the most significant effects on embryonic fate [1]. In the early embryonic stages of development, cells differ in their threshold of sensitivity to endogenous and exogenous factors [2]. However, to preserve and maintain the integrity of the genome, cells activate complex DNA repair mechanisms. It is believed that all major DNA repair pathways function in embryos. Repair proteins interact with cell cycle control proteins to stop the cell cycle if DNA is damaged, allowing the repair complexes time to fix the damaged DNA. If the damage is too substantial, and it is impossible to repair the DNA, a proapoptotic pathway is activated, resulting in cell death [3]. The mechanisms of regulation and functioning of repair systems are well studied in somatic cells. However, less is known about their activities during early embryonic development. Several reports have shown that early embryos and embryonic stem (ES) cells lack functional cell cycle control checkpoints, and DNA synthesis and cell division continue in the presence of damaged DNA. Ineffective activation of cell cycle checkpoints and suppression of apoptotic pathways in early embryos is associated with a shortened cell cycle, helping to ensure that the first embryonic cell division occurs, even under adverse conditions [4]. Thus, this review aims to analyze the literature and compare the role of repair systems at different stages of early mammalian embryonic development from the oocyte to the preimplantation blastocyst. 2. Oocyte Repair Oocytes are one of the longest-living cells in the body, remaining at rest for many months (mouse) or decades (humans) [5]. During this time, they are exposed to exogenous and endogenous factors that cause damage to the DNA structure. DNA double strand breaks (DSBs) accumulate with age in Genes 2020, 11, 1138; doi:10.3390/genes11101138 www.mdpi.com/journal/genes Genes 2020, 11, x FOR PEER REVIEW 2 of 11 2. Oocyte Repair Genes 2020, 11, 1138 2 of 11 Oocytes are one of the longest‐living cells in the body, remaining at rest for many months (mouse) or decades (humans) [5]. During this time, they are exposed to exogenous and endogenous primaryfactors folliclethat cause oocytes damage due to to the cellular DNA metabolism structure. DNA and oxidative double strand stress breaks [6]. Factors (DSBs) such accumulate as γ-radiation, with chemotherapy,age in primary and follicle adverse oocytes environmental due to cellular influences metabolism lead toand the oxidative formation stress of DSBs [6]. Factors in oocytes such during as γ‐ theradiation, primary chemotherapy, follicular stage [and7–9]. adverse In each ofenvironmental these cases, DSBs influences induce lead oocyte to deaththe formation if the damaged of DSBs DNA in isoocytes not repaired. during This the primary leads to follicular depletion stage of the [7–9]. oocyte In each pool of in these the follicles, cases, DSBs premature induce ovarianoocyte death failure, if infertility,the damaged and earlyDNA menopause. is not repaired. Primary This follicularleads to oocytesdepletion at of the the germinal oocyte vesiclepool in (GV) the stagefollicles, are morepremature susceptible ovarian to DNA-damaging failure, infertility, agents and and early are more menopause. prone to apoptosisPrimary follicular compared oocytes to somatic at cellsthe andgerminal more mature vesicle MII(GV) stage stage oocytes are more [10 susceptible]. This might to beDNA associated‐damaging with agents the development and are more of prone a highly to sensitiveapoptosis apoptotic compared response to somatic since cells it is and crucial more to mature eliminate MII stage oocytes oocytes with damaged[10]. This might DNA be to associated protect the germlinewith the [development11]. Therefore, of DNAa highly damage sensitive control apoptotic checkpoints response are since activated it is crucial when to the eliminate cell cycle oocytes stops duringwith damaged meiosis I,DNA facilitating to protect removal the germline of oocytes [11]. with Therefore, DNA that DNA has damage not been control restored checkpoints after meiotic are recombination.activated when Members the cell cycle of the stops p53 during family meiosis have been I, facilitating identified removal as critical of oocytes regulators with of DNA apoptosis that activityhas not in been oocytes restored during after the meiotic GV stage recombination. [12]. According Members to published of the p53 data, family the TAp63have beengene identified is highly as critical regulators of apoptosis activity in oocytes during the GV stage [12]. According to published expressed in primary follicle oocytes and is an essential mediator of induced DNA damage response data, the TAp63 gene is highly expressed in primary follicle oocytes and is an essential mediator of in oocytes due to transcriptional activation of proapoptotic members of the Bcl-2 family, PUMA and induced DNA damage response in oocytes due to transcriptional activation of proapoptotic members NOXA [13]. Interestingly, TAp63 expression is suppressed when oocytes exit the follicle, which may of the Bcl‐2 family, PUMA and NOXA [13]. Interestingly, TAp63 expression is suppressed when partially explain why mature MII oocytes are more resistant to apoptosis due to DNA damage than oocytes exit the follicle, which may partially explain why mature MII oocytes are more resistant to oocytes in the GV stage (Figure1)[14]. apoptosis due to DNA damage than oocytes in the GV stage (Figure 1) [14]. FigureFigure 1. 1.The The process process of of di differentiationfferentiation inin femalefemale germgerm cells.cells. Created with BioRender.com.BioRender.com. Furthermore,Furthermore, mature mature MII MII oocytes oocytes havehave aa broaderbroader expressionexpression profileprofile of mRNA encoding encoding repair repair proteinsproteins compared compared to to GV GV oocytes. oocytes. Nevertheless, Nevertheless, startingstarting from the oocyte at the GV GV stage, stage, expression expression ofof genes genes encoding encoding proteins proteins for for all all repair repair systems systems hashas beenbeen observedobserved [[15].15]. Extensive expression expression of of repairrepair genes genes corresponds corresponds to theto the oocyte’s oocyte’s ability ability to recognize to recognize and repairand repair DNA DNA damage damage from the from earliest the stagesearliest of stages development of development [16]. In 2009, [16]. JaroudiIn 2009, etJaroudi al. demonstrated et al. demonstrated that in humans, that in humans, mRNA mRNA levels of levels most repairof most genes repair in genes oocytes in oocytes are higher are thanhigher in than blastocysts, in blastocysts, which which is explained is explained by the by accumulation the accumulation of a suofffi acient sufficient amount amount of mRNA of mRNA to ensure to ensure preservation preservation of the genome of the genome before and before after and fertilization after fertilization until the zygoticuntil the genome zygotic is genome activated is activated [17]. DNA [17]. repair DNA transcripts repair transcripts that accumulate that accumulate in human in oocyteshuman oocytes play an essentialplay an role essential in chromatin role in remodeling chromatin andremodeling maintenance and ofmaintenance chromatin integrity of chromatin during integrity fertilization during [18]. Transcriptsfertilization of [18]. all DNA Transcripts repair pathways, of all DNA including repair basepathways, excision including repair (BER), base mismatch excision repair (MMR),(BER), nucleotidemismatch excisionrepair (MMR), repair (NER),nucleotide double excision strand repair break (NER), (DSBs) double repair strand are presented break (DSBs) in oocytes repair at are the GVpresented and MII in stages oocytes in mouse,at the GV monkey, and MII
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