p53 responsive elements in human retrotransposons.
Long interspersed nuclear elements-1 (L1s) are highly repetitive DNA elements that are capable of altering the human genome through retrotransposition. To protect against L1 retroposition, the cell downregulates the expression of L1 proteins by various mechanisms, including high-density cytosine methylation of L1 promoters and DICER-dependent destruction of L1 mRNAs. In this report, a large number of p53 responsive elements, or p53 DNA binding sites, were detected in L1 elements within the human genome. At least some of these p53 responsive elements are functional and can act to increase the levels of L1 mRNA expression. The p53 protein can directly bind to a short 15-nucleotide sequence within the L1 promoter. This p53 responsive element within L1 is a recent addition to evolution, appearing approximately 20 million years ago. This suggests an interplay between L1 elements, which have a rich history of causing changes in the genome, and the p53 protein, the function of which is to protect against genomic changes. To understand these observations, a model is proposed in which the increased expression of L1 mRNAs by p53 actually increases, rather than decreases, the genomic stability through amplification of p53-dependent processes for genomic protection.
Harris
C R
CR
Raymond and Beverly Sackler Foundation, New Brunswick, NJ 08540, USA.
Dewan
A
A
Zupnick
A
A
Normart
R
R
Gabriel
A
A
Prives
C
C
Levine
A J
AJ
Hoh
J
J
D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000502:physiology; D019143:Evolution, Molecular; D005786:Gene Expression Regulation / Q000502:physiology; D015894:Genome, Human / Q000502:physiology*; D042822:Genomic Instability / Q000502:physiology*; D006801:Humans; D020084:Long Interspersed Nucleotide Elements / Q000502:physiology*; D008957:Models, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020218:Response Elements / Q000502:physiology*; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D043244:Ribonuclease III