DNA repair disorders causing malformations

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DNA damage contributes significantly to the abnormal development or demise of the conceptus. The widely differing phenotypes that result from mutations in DNA repair genes suggest that these genes play critical roles during development, even in the absence of exogenous DNA-damaging agents. Molecules that sense DNA damage and regulate DNA repair, cell cycle checkpoints and apoptosis act as teratogen suppressor genes, protecting the conceptus against insult from DNA damaging teratogens.

Introduction

DNA damage in the conceptus might result in embryo death, growth retardation or malformations. In humans, 40–75% of fertilized ova are wasted; early spontaneous abortions, many with chromosomal abnormalities, contribute to almost half of these losses [1]. Approximately 3% of all liveborn infants have a malformation apparent at birth; of these malformations, an estimated 50–60% are of unknown aetiology, and 20% are caused by a chromosomal aberration or gene mutation [2]. DNA damage might be spontaneous or be triggered by an exposure that has a direct effect on DNA or that generates reactive oxygen species. Well-established teratogenic exposures (see Glossary), such as ethanol, phenytoin, thalidomide, hyperglycemia, and anticancer drugs, or deficiencies in essential substances, such as folates, produce DNA damage, either directly or as a result of oxidative stress [3, 4].

Mammalian cells have evolved complex mechanisms to detect DNA damage and to trigger the responses needed to maintain genomic integrity; these include DNA damage sensor mechanisms, DNA repair, cell cycle arrest and apoptosis. During development, both the nature of DNA damage and the ability of the conceptus to respond are likely to determine the outcome [5]. There are at least 15 known human genetic disorders associated with defects in the response to DNA damage [6]. Although an increased predisposition to cancer is a general feature of these disorders, some are associated with developmental defects. A recent database lists 141 mouse mutant strains with defective cellular responses to DNA damage [7]. Targeted deletion of several of these genes results in embryolethality (see Glossary); others are viable but display an increased sensitivity to genotoxic exposures and an incidence of tumors.

The goal of this review is to highlight recent advances in our understanding of the role of DNA damage and the response to such damage in determining the fate of the conceptus.

Section snippets

DNA repair

Sophisticated DNA repair pathways have evolved to maintain genetic integrity in the face of constant bombardment by spontaneously generated free radicals and exogenous compounds. DNA repair pathways have been reviewed extensively [8, 9]. There are four main DNA repair pathways in mammalian cells: the nucleotide excision repair (NER) pathway, which repairs the majority of DNA damage in cells; the mismatch repair (MMR) pathway, which repairs mispairs caused by errors in DNA replication; the base

Nucleotide excision repair

NER is an active process, requiring the concerted step-wise effort of 20–30 different polypeptides. DNA damage recognition in transcription-coupled NER is thought to involve arrest of the transcriptional machinery. The expression of different NER genes is regulated in a developmental stage- and tissue-specific manner during the organogenesis stage in the rat conceptus [10]. Mutations in NER genes are responsible for the majority of human DNA repair genetic disorders, including xeroderma

Mismatch repair

Mutations in human MMR genes produce Lynch syndrome, conferring a predisposition to colorectal cancer and other extracolonic cancers [16]. Mice with mutations in MMR genes are usually viable, despite an increased incidence of base mutations; in some strains meiosis is defective, resulting in sterility [7•, 17]. Recently, DNA methyltransferase 1 (Dnmt1) was identified as a MMR gene [18]. Loss of Dnmt1 is lethal in mid-organogenesis [19]. Dnmt1-deficient embryonic stem cells exhibit

Base excision repair

BER is responsible for removing damaged, potentially highly mutagenic, bases, such as 8-oxo-7,8-dihydroguanine. Interestingly, folate deficiency, associated with an increased incidence of neural tube defects, results in a functional BER deficiency by stimulating BER initiation and the accumulation of toxic repair intermediates in the form of DNA single strand breaks [21]. The chemical induction of folate deficiency, by exposing embryos during organogenesis to methotrexate, a dihydrofolate

Double strand break repair

DNA DSBs are one of the most severe forms of DNA damage, serving as potent triggers of cell cycle arrest and apoptosis [24]. During repair by homologous recombination (HR), the damaged chromosome enters into physical contact with an undamaged DNA molecule with which it shares sequence homology and which it uses as a template for repair. HR is thought to be error-free and occurs predominantly during meiosis and when sister chromatids are available in late S/G2. Non-homologous end-joining (NHEJ)

The phosphatidylinositol 3-kinase signal cascade

The phosphatidylinositol 3-kinase (PI3-K) signal cascade and the ADP-ribosylation of proteins are both important in sensing DNA damage and integrating the repair response. Ataxia-telangiectasia mutated (ATM), ataxia-telangiectasia (A-T) and Rad3-related (ATR) are PI3-K family members serving as damage sensors and signal transducers that regulate cell cycle checkpoints and DNA repair by phosphorylating proteins such as NBS1, CHK1, CHK2 and p53, a tumour suppressor gene [33]. In humans, lack of

Conclusions

The impact on the embryo of a deficiency in the ability to respond to DNA damage is highly variable. Mutations in some DNA repair pathways do not have an observable phenotype during development, whereas others lead to embryolethality and malformations, even in the absence of exogenous DNA-damaging agents. Why are the consequences so variable? The first and most apparent answer is that some pathways or repair genes are essential during development and others are not. Many of the enzymes involved

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

In many instances, it has been necessary to reference reviews rather then the original articles owing to space limitations. I apologize to the many authors of outstanding papers that were not included here.

Glossary

Apurinic/apyrimidinic endonuclease
Apex or APE/REF-1 is an enzyme known to cut DNA when a purine or pyrimidine is missing.
Ataxia
A loss of voluntary muscle coordination.
Aneuploid cells
Cells with an abnormal number of chromosomes.
Embryolethality
Death of the embryo. The embryo is the developing organism from the stage after the appearance of the long axis until all major anatomical structures are present. In humans, this is from about the second week after fertilization until about the end of the

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