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DNA Repair and Carcinogenesis
Published in Philip L. Grover, Chemical Carcinogens and DNA, 2019
In these experiments DNA, newly synthesized during semiconservative replication, is labeled by a short pulse soon after exposure to the agent, and its initial size is determined. Then DNA synthesis is allowed to continue for several hours in the absence of label (chase), and the original pulse-labeled DNA is again examined for size using alkaline sucrose gradients or similar techniques. Pulse-labeled DNA is eventually found to reach the size of the DNA from untreated cells. Since there is good evidence in bacteria that daughter strands of DNA made from UV-irradiated templates contain gaps (Figure 1C), Lehmann suggested that in UV-irradiated mammalian cells similar gaps are left in daughter strands when the DNA polymerase encounters a blocking lesion.72 The fact that the smaller DNA eventually reaches the size of DNA from unirradiated control cells suggests that during the chase such gaps are filled in some way. He72 and others73,74,77 could find no evidence that the gaps were filled by physical exchange between parental strands and daughter strands, and suggested, rather, that de novo synthesis is involved. If radioactive, pulse-labeled, low-molecular-weight DNA is chased in the presence of BUdR and then the DNA is subjected to 313-nm photolysis, its size is reduced once again to the original low molecular weight. This supports the hypothesis that the original shorter segments were interrupted by gaps which got filled by de novo synthesis utilizing the BUdR.
Cell division
Published in Frank J. Dye, Human Life Before Birth, 2019
In a population of dividing (called cycling) cells, each cell passes through four consecutive stages: G1, S, G2, and M (gap 1, DNA synthesis, gap 2, and mitosis). During G1, preparations are made for DNA synthesis; this is the stage that usually occupies the longest portion of the cell cycle. Also, differences in the duration of cell cycles between different kinds of cells can usually be attributed to differences in the duration of G1. DNA undergoes a process called semiconservative replication during the S stage. The two complementary strands of the mother cell's DNA separate, and each one acts as a template (a guide; see details in Chapter 4) for a new complementary strand. Barring mutations, two complete identical copies of the original DNA are formed (Figure 3.2).
Molecular Biology
Published in John C Watkinson, Raymond W Clarke, Louise Jayne Clark, Adam J Donne, R James A England, Hisham M Mehanna, Gerald William McGarry, Sean Carrie, Basic Sciences Endocrine Surgery Rhinology, 2018
Michael Kuo, Richard M. Irving, Eric K. Parkinson
During normal cell division, DNA replication is achieved by the separation of the two strands by DNA helicase. Each separated single strand then acts as a template for polymerization, catalyzed by DNA polymerase, of nucleotides forming a new complementary strand and thus double-stranded DNA identical to the original dsDNA. As each daughter DNA consists of one original and one newly synthesized DNA strand, the process is known as semi-conservative replication. The specificity of the complementary relationship between the nucleotides on each strand forms the basis for many techniques of modern molecular biology and molecular cytogenetics.1 The accuracy with which DNA replication takes place is remarkable with an estimated error rate of less than one in 109 nucleotide additions. Such accuracy is of vital importance to the individual as a permanent change in DNA, or mutation may cause inactivation of a gene essential to cell survival or cell cycle control. The high fidelity of DNA sequence replication is achieved by unidirectional 5’-to-3’ direction of DNA replication, a rigorous DNA proofreading mechanism that detects mismatched DNA and efficient DNA repair pathways that excise and repair DNA damage. Failure of these mechanisms, such as is encountered in xeroderma pigmentosum, Fanconi’s anaemia and ataxia telangiectasia, leads to accumulation of DNA replication errors and a high incidence of malignancies.
Cutis marmorata telangiectatica congenita: a focus on its diagnosis, ophthalmic anomalies, and possible etiologic factors
Published in Ophthalmic Genetics, 2020
Matthew S. Elitt, Joan E. Tamburro, Rocio T. Moran, Elias Traboulsi
In 1986 Rudolf Happle postulated the complex mechanism of mosaicism with embryonically lethal genetic mutations, providing an explanation for the unusual cutaneous disease patterns and non-mendelian inheritance seen in several disorders, including CMTC (39). In this concept, an embryonically lethal dominant or recessive mutation would emerge in a cell at the post-zygotic stage through a spontaneous mutation or semiconservative replication of a half-chromatid mutation, creating a mosaic embryo containing both genetically normal and abnormal tissues. Critically, Happle claimed that this unique developmental timeline would protect the embryo from mutation-induced fetal demise while also presenting a heritability block due to the embryonic lethality when present at the zygotic stage. Collectively, this idea could explain two prominent features of CMTC: (1) The presence of normal tissue outside of the vascular lesions and (2) non-mendelian inheritance patterns (5). However, rare reports of generational inheritance (40) and CMTC in sibling family members (41) present problems for this etiologic explanation which is predicated on a lack of heritability. To address this apparent conflict, Danarti, Konig, and Happle suggested a paradominant mode inheritance for CMTC (31,42), representing a slight modification to Happle’s original mosaicism model. In this idea mutations would be embryonically lethal when homozygous but tolerated when heterozygous, allowing for generational inheritance in carriers but precluding the emergence of non-mosaic, homozygous individuals. Similar to Happle’s original proposal, if a loss of heterozygosity occurred at a post-zygotic stage due to recombination, gene conversion, or a spontaneous mutation (43), and generated a mosaic embryo containing both genetically normal and abnormal tissue, the mutant cells could be tolerated (31). As such this could explain the potential for rare inheritance in CMTC while still satisfying non-mendelian inheritance and cutaneous lesion patterns seen in the disease.
An update on the biology and management of dyskeratosis congenita and related telomere biology disorders
Published in Expert Review of Hematology, 2019
Marena R. Niewisch, Sharon A. Savage
Telomere structure poses two main challenges related to DNA repair and replication: 1) they may be recognized by DNA damage repair machinery as double-stranded DNA breaks, and 2) the ‘end replication problem’ that results in ongoing telomere nucleotide repeat loss due to semiconservative replication of DNA ends during DNA replication.