It is commonly accepted that the reverse-transcribed cellular RNA molecules, called retroposons, integrate at staggered breaks in mammalian chromosomes. However, unlike what was previously thought, most of the staggered breaks are not generated by random nicking. One of the two nicks involved is primarily associated with the 5′-TTAAAA hexanucleotide and its variants derived by a single base substitution, particularly A → G and T → C. It is probably generated in the antisense strand between the consensus bases 3′-AA and TTTT complementary to 5′-TTAAAA. The sense strand is nicked at variable distances from the TTAAAA consensus site toward the 3′ end, preferably within 15–16 base pairs. The base composition near the second nicking site is also nonrandom at positions preceding the nick. On the basis of the observed sequence patterns it is proposed that integration of mammalian retroposons is mediated by an enzyme with endonucleolytic activity. The best candidate for such enzyme may be the reverse transcriptase encoded by the L1 non-long-terminal-repeat retrotransposon, which contains a freshly reported domain homologous to the apurinic/apyrimidinic (AP) endonuclease family [Martin, F., Olivares, M., Lopez, M. C. & Alonso, C. (1996) Trends Biochem. Sci. 21, 283–285; Feng, Q., Moran, J. V., Kazazian, H. H. & Boeke, J. D. (1996) Cell 87, 905–916] and shows nicking in vitro with preference for targets similar to 5′-TTAAAA/3′-AATTTT consensus sequence [Feng, Q., Moran, J. V., Kazazian, H. H. & Boeke, J. D. (1996) Cell 87, 905–916]. A model for integration of mammalian retroposons based on the presented data is discussed
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