Hybridization between mitochondrial heavy strand tDNA and expressed light strand tRNA modulates the function of heavy strand tDNA as light strand replication origin.
Mitochondrial heavy strand (HS) tDNA codes for tRNAs and frequently functions as the light strand (LS) replication origin (OL). During replication, HS sites remain single-stranded until their LS complement is synthesized, a state prone to hydrolytic deaminations of C-->T and A-->G, causing genome-wide deamination gradients starting at OLs and proportional to time spent single-stranded. Gradient strength is proportional to OL formation by HS tDNAs. Hypothetically, hybridization between HS tDNA and its expressed complement tRNA should decrease OL activity for LS-, but not HS-encoded tRNAs. Comparisons between primate genomes and between pathogenic and non-pathogenic human polymorphisms both confirm corresponding predictions on OL activity. In primates, strengths of deamination gradients starting at tDNAs functioning as OLs and coding for LS tRNAs decrease proportionally to stabilities of HS tDNA-LS tRNA hybridization; not so for HS tRNAs. Similarly, in mutants of human HS tDNAs coding for LS tRNAs, pathogenic mutants of tDNAs usually not forming OLs form weaker HS tDNA-LS tRNA duplexes than non-pathogenic ones; the opposite is true for tDNAs usually forming OLs. No trend was detected for HS tDNA coding for HS tRNA. tDNA-tRNA hybridization of the modal (most frequent) human tDNA sequence is more stable than of other, rarer non-pathogenic polymorphisms, suggesting similar but weaker mutational effects on tDNA/tRNA functions than in pathogenic mutants. HS tDNA-LS tRNA hybridization appears to compete with OL formation by HS tDNA self-hybridization.
Seligmann
Hervé
H
Department of Evolution, Systematics and Ecology, The Hebrew University of Jerusalem, 91904, Israel. hselig1@yahoo.com
D000818:Animals; D004261:DNA Replication; D004272:DNA, Mitochondrial / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004277:DNA, Single-Stranded / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003641:Deamination; D016678:Genome; D006801:Humans; D009154:Mutation; D009690:Nucleic Acid Conformation; D009693:Nucleic Acid Hybridization; D011110:Polymorphism, Genetic; D014176:Protein Biosynthesis / Q000235:genetics; D012343:RNA, Transfer / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018741:Replication Origin
D004272:DNA, Mitochondrial; D004277:DNA, Single-Stranded; D012343:RNA, Transfer