SEQUENCE PATTERNS INDICATE AN ENZYMATIC INVOLVEMENT IN INTEGRATION OFMAMMALIAN RETROPOSONS

It is commonly accepted that the reverse-transcribed cellular RNA mole cules, called retroposons, integrate at staggered breaks in mammalian chromosomes, However, unlike what was previously thought, most of the staggered breaks are nor generated by random nicking, One of the two n icks involved is primarily associated with the 5'-TTAAAA hexanucleotid e 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 con sensus site toward the 3' end, preferably within 15-16 base pairs, The base composition near the second nicking site is also nonrandom at po sitions preceding the nick On the basis of the observed sequence patte rns it is proposed that integration of mammalian retroposons is mediat ed by an enzyme with endonucleolytic activity, The best candidate for such enzyme may be the reverse transcriptase encoded by the L1 non-lon g-terminal-repeat retrotransposon, which contains a freshly reported d omain homologous to the apurinic/apyrimidinic (AP) endonuclease family [Martin, F., Olivares, M., Lopez, M. C. & Alonso, C. (1996) Trends Bi ochem. Sci, 21, 283-285; Feng, Q., Moran, J. V., Kazazian, H. H. & Boe ke, J. D. (1996) Cell 87, 905-916] and shows nicking in vitro with pre ference 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.