Impairment of BRCA1-Related DNA Double-Strand Break Repair Leads to Ovarian Aging in Mice and Humans

Titus, Shiny; Li, Fang; Stobezki, Robert; Akula, Komala; Ünsal, Evrim; Jeong, Kyoung Sook; Dickler, Maura N.; Robson, Mark E.; Moy, Fred; Goswami, Sumanta; Oktay, Kutluk

doi:10.1126/scitranslmed.3004925

Cited by 404 publications

(463 citation statements)

References 63 publications

(93 reference statements)

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“…If, as seems likely, gametes and zygotes endure an increased number of DSBs during meiotic recombination and segregation, an efficient genome repair capacity would be critical 33 and unique zygotic DNA repair machinery might rely entirely on maternal oocyte factors deposited and stored during maturation since zygotes are transcriptionally silent. Recent studies suggest that oocytes might employ an ataxia-telangiectasia mutated (ATM)-mediated DNA damage signalling (DDS) pathway that regulates repair of DSBs via a homologous recombination mechanism 34 . Thus, Cas9-induced DNA breaks are likely to attract the existing native oocyte machinery reserved for repair of meiotic recombinationinduced DSBs.…”

Section: Discussionmentioning

confidence: 99%

Correction of a pathogenic gene mutation in human embryos

Martí-Gutiérrez

Park

et al. 2017

Nature

799

545

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More than 10,000 monogenic inherited disorders have been identified, affecting millions of people worldwide. Among these are autosomal dominant mutations, where inheritance of a single copy of a defective gene can result in clinical symptoms. Genes in which dominant mutations manifest as late-onset adult disorders include BRCA1 and BRCA2, which are associated with a high risk of breast and ovarian cancers 1 , and MYBPC3, mutation of which causes hypertrophic cardiomyopathy (HCM) 2 . Because of their delayed manifestation, these mutations escape natural selection and are often transmitted to the next generation. Consequently, the frequency of some of these founder mutations in particular human populations is very high. For example, the MYBPC3 mutation is found at frequencies ranging from 2% to 8% 3 in major Indian populations, and the estimated frequency of both BRCA1 and BRCA2 mutations among Ashkenazi Jews exceeds 2% 4 .HCM is a myocardial disease characterized by left ventricular hypertrophy, myofibrillar disarray and myocardial stiffness; it has an estimated prevalence of 1:500 in adults 5 and manifests clinically with heart failure. HCM is the commonest cause of sudden death in otherwise healthy young athletes. HCM, while not a uniformly fatal condition, has a tremendous impact on the lives of individuals, including physiological (heart failure and arrhythmias), psychological (limited activity and fear of sudden death), and genealogical concerns. MYBPC3 mutations account for approximately 40% of all genetic defects causing HCM and are also responsible for a large fraction of other inherited cardiomyopathies, including dilated cardiomyopathy and left ventricular non-compaction 6 . MYBPC3 encodes the thick filament-associated cardiac myosin-binding protein C (cMyBP-C), a signalling node in cardiac myocytes that contributes to the maintenance of sarcomeric structure and regulation of both contraction and relaxation 2 .Current treatment options for HCM provide mostly symptomatic relief without addressing the genetic cause of the disease. Thus, the development of novel strategies to prevent germline transmission of founder mutations is desirable. One approach for preventing second-generation transmission is preimplantation genetic diagnosis (PGD) followed by selection of non-mutant embryos for transfer in the context of an in vitro fertilization (IVF) cycle. When only one parent carries a heterozygous mutation, 50% of the embryos should be mutationfree and available for transfer, while the remaining carrier embryos are discarded. Gene correction would rescue mutant embryos, increase the number of embryos available for transfer and ultimately improve pregnancy rates.Recent developments in precise genome-editing techniques and their successful applications in animal models have provided an option for correcting human germline mutations. In particular, CRISPR-Cas9 is a versatile tool for recognizing specific genomic sequences and inducing DSBs 7-10 . DSBs are then resolved by endogenous DNA repair mechanisms, prefer...

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Section: Discussionmentioning

confidence: 99%

Correction of a pathogenic gene mutation in human embryos

Martí-Gutiérrez

Park

et al. 2017

Nature

799

545

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“…48 Interestingly, expression of several players in DSBs repair (e.g., BRCA1, MRE11 and RAD51) decreases with age in human and mouse oocytes. 17 This decrease could compromise DNA repair and genome integrity in both growing and maturing oocytes and thereby result in reduced fertility.…”

Section: Discussionmentioning

confidence: 99%

“…15 DNA integrity in oocytes is essential for reproduction. 11,16,17 Thus, it is unclear why the DNA damage threshold for checkpoint activation in full-grown prophase I oocytes seems elevated. A possible explanation is that there may be a selective advantage to repair the damage later during the cell cycle rather than activate the checkpoint during resumption of meiosis.…”

Section: Introductionmentioning

confidence: 99%

DNA damage response during mouse oocyte maturation

Mayer

Baran

Sakakibara³

et al. 2016

Cell Cycle

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Because low levels of DNA double strand breaks (DSBs) appear not to activate the ATM-mediated prophase I checkpoint in full-grown oocytes, there may exist mechanisms to protect chromosome integrity during meiotic maturation. Using live imaging we demonstrate that low levels of DSBs induced by the radiomimetic drug Neocarzinostatin (NCS) increase the incidence of chromosome fragments and lagging chromosomes but do not lead to APC/C activation and anaphase onset delay. The number of DSBs, represented by gH2AX foci, significantly decreases between prophase I and metaphase II in both control and NCS-treated oocytes. Transient treatment with NCS increases >2-fold the number of DSBs in prophase I oocytes, but less than 30% of these oocytes enter anaphase with segregation errors. MRE11, but not ATM, is essential to detect DSBs in prophase I and is involved in H2AX phosphorylation during metaphase I. Inhibiting MRE11 by mirin during meiotic maturation results in anaphase bridges and also increases the number of gH2AX foci in metaphase II. Compromised DNA integrity in mirin-treated oocytes indicates a role for MRE11 in chromosome integrity during meiotic maturation.

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“…We can hypothesize that the increase in FA is owing to the reduction in egg quality during ageing [31,32], a decline caused by damaged RNAs and proteins. Furthermore, instability could also result from the accumulation of DNA damage in gametes, a process that occurs both in humans [33][34][35] and flies [36]. Interestingly, it was recently shown that eggs from D. melanogaster females fed with a poor diet were deficient in correcting damage in sperm DNA [37].…”

Section: Discussionmentioning

confidence: 99%

Parental age influences developmental stability of the progeny inDrosophila

et al. 2015

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The stochastic nature of biochemical processes is a source of variability that influences developmental stability. Developmental instability (DI) is often estimated through fluctuating asymmetry (FA), a parameter that deals with withinindividual variation in bilateral structures. A relevant goal is to shed light on how environment, physiology and genotype relate to DI, thus providing a more comprehensive view of organismal development. Using Drosophila melanogaster isogenic lines, we investigated the effect of parental age, parental diet and offspring heterozygosity on DI. In this work, we have uncovered a clear relationship between parental age and offspring asymmetry. We show that asymmetry of the progeny increases concomitantly with parental age. Moreover, we demonstrate that enriching the diet of parents mitigates the effect of age on offspring symmetry. We show as well that increasing the heterozygosity of the progeny eliminates the effect of parental age on offspring symmetry. Taken together, our results suggest that diet, genotype and age of the parents interact to determine offspring DI in wild populations. These findings provide us with an avenue to understand the mechanisms underlying DI.

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Impairment of BRCA1-Related DNA Double-Strand Break Repair Leads to Ovarian Aging in Mice and Humans

Cited by 404 publications

References 63 publications

Correction of a pathogenic gene mutation in human embryos

Correction of a pathogenic gene mutation in human embryos

DNA damage response during mouse oocyte maturation

Parental age influences developmental stability of the progeny inDrosophila

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