Rejoining of DNA strand breaks

Administration of dipyridamole-AMP to mice 5—25 min after 1 Gy (100 rad) of TBI y-kradiation is also protective, as indicated by plasma thymidine levels and the amount of saline soluble polynucleotides in the thymus (112). Adding dipyridamole-AMP to in vitro kradiated suspensions of thymocytes enhances the rejoining of DNA strand breaks (112). These post-kradiation effects ate presumably mediated by the activation of extraceUulat adenosine receptors. 

Johnstone AP (1984) Rejoining of DNA strand breaks is an early event during the stimulation of quiescent lymphocytes. Eur J Biochem 140 401-406... 

McWilliams RS, Cross WG, Kaplan JG, Birnboim HC (1983) Rapid rejoining of DNA strand breaks in resting human lymphocytes after irradiation by low doses of Co 7 rays or 14.6 MeU neutrons. Radiat Res 94 499-507... 

Requirement for ADP-Ribosyltransferase Activity and Rejoining of DNA Strand Breaks During Lymphocyte Stimulation... 

In performing its role in the cleavage and rejoining of DNA strands (catenation, decatenation, relaxation, unknotting), topoisomerase II bonds to the 5 -phosphate on adjacent DNA strands four base pairs apart to form an enzyme-DNA complex. It is the interaction between this complex and certain drugs, such as ellipticine (1), that results in the stabilization of the complex and the formation of a cleavable complex which leads eventually to the cleavage of double-stranded DNA. Pommier et al. 157,158) have shown that low concentrations of elliptinium (5) (<10 xAf) produce DNA double-strand breaks in mammalian cells, but higher concentrations (>10 pAf) produce no such breaks and, in fact. 

It was first shown in S. Shall s laboratory that the nicotinamide analog aminobenzamide leads to an increase of the steady state concentration of DNA strand breaks during DNA repair [1,2]. This phenomenon has been explained by a decreased rejoining rate. 

Two proteins are initially involved in the nonho-mologous rejoining of a ds break. Ku, a heterodimer of 70 kDa and 86 kDa subunits, binds to free DNA ends and has latent ATP-dependent helicase activity. The DNA-bound Ku heterodimer recruits a unique protein kinase, DNA-dependent protein kinase (DNA-PK). DNA-PK has a binding site for DNA free ends and another for dsDNA just inside these ends. It therefore allows for the approximation of the two separated ends. The free end DNA-Ku-DNA-PK complex activates the kinase activity in the latter. DNA-PK reciprocally phos-phorylates Ku and the other DNA-PK molecule, on the opposing strand, in trans. DNA-PK then dissociates from the DNA and Ku, resulting in activation of the Ku helicase. This results in unwinding of the two ends. The unwound, approximated DNA forms base pairs the extra nucleotide tails are removed by an exonucle-... 

These observations regarding DNA strand-breaks are at most, suggestive that perhaps the molecular mechanism of ADPRT action in cell differentiation involves breakage and rejoining of DNA. However, other mechanisms are very plausible. For example, ADP-ribosylation may be required because of its effect on chromatin conformation, or specific regulatory chromatin proteins may be ADP-ribosylated as a signal for the induction of a previously non-expressed gene. 

Taucher-Scholz G, Heilmann J, Kraft G (1996) Induction and rejoining of DNA double-strand breaks in CHO cells after heavy ion irradiation. Adv Space Res 18 83-92 Toulany M, Dittmann K, Kruger M et al (2005) Radioresistance of K-Ras mutated human tumor cells is mediated through EGFR-dependent activation of PI3K-AKT pathway. Radiother Oncol 76 143-150... 

Topoisomerase enzymes (topoisomerases I and II) are enzymes that control the changes in DNA structure by breaking and rejoining the phosphodiester backbone of DNA strand during the normal cell cycles. Topoisomerases have become popular targets for cancer chemotherapy drugs. 

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