Mechanisms of Ageing and Development

Committee on Genetics, University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USA
Mechanisms of Ageing and Development (Impact Factor: 3.4). 07/2008; 129(7-8):425-40. DOI: 10.1016/j.mad.2008.03.003
Source: PubMed


Homologous recombination (HR) is a genetic mechanism in somatic cells that repairs DNA double-strand breaks and restores productive DNA synthesis following disruption of replication forks. Although HR is indispensable for maintaining genome integrity, it must be tightly regulated to avoid harmful outcomes. HR-associated genomic instabilities arise in three human genetic disorders, Bloom syndrome (BS), Werner syndrome (WS), and Rothmund-Thomson syndrome (RTS), which are caused by defects in three individual proteins of the RecQ family of helicases, BLM, WRN, and RECQL4, respectively. Cells derived from persons with these syndromes display varying types of genomic instability as evidenced by the presence of different kinds of chromosomal abnormalities and different sensitivities to DNA damaging agents. Persons with these syndromes exhibit a variety of developmental defects and are predisposed to a wide range of cancers. WS and RTS are further characterized by premature aging. Recent research has shown many connections between all three proteins and the regulation of excess HR. Here, we illustrate the elaborate networks of BLM, WRN, and RECQL4 in regulating HR, and the potential mechanistic linkages to cancer and aging.

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Available from: Nathan A Ellis, Aug 10, 2015
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    • "RecQ helicases also represent very promising targets for anticancer therapy through DNA repair inhibition. They function in multiple cell processes such as DNA replication, transcription, DNA repair, telomere maintenance and DNA damage signaling [193] [194] [195] [196]. "
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    ABSTRACT: Genomic DNA is constantly challenged from endogenous as well as exogenous sources. The DNA damage response (DDR) mechanism has evolved to combat these challenges and ensure genomic integrity. In this review, we will focus on repair of DNA double-strand breaks (DSB) by homologous recombination and the role of several nucleases and other recombination factors as suitable targets for cancer therapy. Their inactivation as well as overexpression have been shown to sensitize cancer cells by increasing toxicity to DNA-damaging agents and radiation or to be responsible for resistance of cancer cells. These factors can also be used in targeted cancer therapy by taking advantage of specific genetic abnormalities of cancer cells that are not present in normal cells and that result in cancer cell lethality.
    FEBS Letters 06/2014; 588(15). DOI:10.1016/j.febslet.2014.06.010 · 3.17 Impact Factor
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    • "These data, together with the putative role for RECQL4 in DNA replication (Liu 2010), suggest that RECQL4 is involved in telomere maintenance during DNA replication, even though the growth rates of RTS cells are within the normal range (this work). As ectopic expression of telomerase in RTS cells successfully produced telomerase activity and resulted in immortalised RTS cells lines, either RECQL4 is dispensable for telomerase activity, or the low levels of RECQL4 thought to be found in RTS cell strains (Ouyang et al. 2008) are sufficient for telomerase activity and telomere maintenance in the presence of high telomerase levels. "
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    ABSTRACT: Rothmund–Thomson fibroblasts had replicative lifespans and growth rates within the range for normal fibroblasts; however, they show elevated levels of the stress-associated p38 MAP kinase, suggestive of stress during growth. Treatment with the p38 MAP kinase inhibitor SB203580 increased both lifespan and growth rate, as did reduction of oxidative stress using low oxygen in some strains. At replicative senescence p53, p21WAF1 and p16INK4A levels were elevated, and abrogation of p53 using shRNA knockdown allowed the cells to bypass senescence. Ectopic expression of human telomerase allowed Rothmund–Thomson fibroblasts to bypass senescence. However, activated p38 was still present, and continuous growth for some telomerised clones required either a reduction in oxidative stress or SB203580 treatment. Overall, the evidence suggests that replicative senescence in Rothmund–Thomson cells resembles normal senescence in that it is telomere driven and p53 dependent. However, the lack of RECQL4 leads to enhanced levels of stress during cell growth that may lead to moderate levels of stress-induced premature senescence. As replicative senescence is believed to underlie human ageing, a moderate level of stress-induced premature senescence and p38 activity may play a role in the relatively mild ageing phenotype seen in Rothmund–Thomson. Electronic supplementary material The online version of this article (doi:10.1007/s11357-012-9476-9) contains supplementary material, which is available to authorized users.
    Journal of the American Aging Association 10/2013; 35(5):DOI: 10.1007/s11357-012-9476-9. DOI:10.1007/s11357-012-9476-9 · 3.39 Impact Factor
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    • "RMPs include phage UvsY (6), prokaryotic RecBCD and RecFOR proteins (7–10) and numerous eukaryotic members (11). Mutations of human RMPs have been found to be associated with cancer predisposition, mental retardation, UV sensitivity and premature aging (12–15). "
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    ABSTRACT: Efficient DNA repair is critical for cell survival and the maintenance of genome integrity. The homologous recombination pathway is responsible for the repair of DNA double-strand breaks within cells. Initiation of this pathway in bacteria can be carried out by either the RecBCD or the RecFOR proteins. An important regulatory player within the RecFOR pathway is the RecOR complex that facilitates RecA loading onto DNA. Here we report new data regarding the assembly of Deinococcus radiodurans RecOR and its interaction with DNA, providing novel mechanistic insight into the mode of action of RecOR in homologous recombination. We present a higher resolution crystal structure of RecOR in an 'open' conformation in which the tetrameric RecR ring flanked by two RecO molecules is accessible for DNA binding. We show using small-angle neutron scattering and mutagenesis studies that DNA binding does indeed occur within the RecR ring. Binding of single-stranded DNA occurs without any major conformational changes of the RecOR complex while structural rearrangements are observed on double-stranded DNA binding. Finally, our molecular dynamics simulations, supported by our biochemical data, provide a detailed picture of the DNA binding motif of RecOR and reveal that single-stranded DNA is sandwiched between the two facing oligonucleotide binding domains of RecO within the RecR ring.
    Nucleic Acids Research 06/2013; 41(16). DOI:10.1093/nar/gkt572 · 9.11 Impact Factor
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