Those retroviruses get everywhere

Genome Endogenous retroviruses (ERVs) have spread through mammalian genomes throughout evolution, resulting in thousands of copies or fragments of ERVs, encompassing an estimated 7% of the human genome. However, despite their abundance, specific functions could only rarely be assigned to ERVs. The LTRs of such viruses can serve as strong promoters/enhancers, boosting the transcription of viral or adjacent cellular genes. In a recent discovery of a pathologic example in humans, the derepression of an LTR was found to induce the driver proto-oncogene CSF1R in Hodgkin’s lymphoma. The promoter activity of LTRs can display various tissue specificities and is sometimes limited to germ cells. For example, an LTR from the human endogenous retrovirus 9 (ERV9) predominantly transcribes in testis.

Maintaining genomic integrity in the germ line is a fundamental prerequisite for the evolutionary stability of a species. To achieve this, germ cells with damaged DNA need to be efficiently eliminated. This elimination is particularly important when an individual’s fertility is maintained over several decades, as is the case in humans and great apes (Hominidae). In these species, the already long time frame of fertility in females is even more extended in males. However, only very limited knowledge exists on how the genomic integrity of the male germ line is controlled and preserved in humans.

p63 is a homolog of the tumor suppressor p53. In somatic cells, p53 is the quintessential mediator of apoptosis in response to DNA damage, thus acting as the guardian of the genome. Tumor suppressor p53 binds and transcriptionally activates multiple proapoptotic genes. Moreover, p53 directly associates with mitochondria, and by interacting with anti- and proapoptotic members of the Bcl2 family of outer membrane permeability regulators, triggers the release of cytochrome c, jumpstarting apoptosis. This paper shows that unique isoforms of p63 are highly and specifically expressed in human testis as a result of an upstream insertion of an ERV9 LTR with strong promoter activity that occurred 10 to 15 million years ago during primate evolution at the branching point to long-lived Hominidae. Upon DNA damage, the resulting germ cell-associated, transcriptionally active p63 suppresses proliferation and induces apoptosis. Conversely, GTAp63 expression is frequently lost in human testicular cancers.

Endogenous retrovirus drives hitherto unknown proapoptotic p63 isoforms in the male germ line of humans and great apes. PNAS USA February 7 2011. doi: 10.1073/pnas.101620110

Related:

This entry was posted in Uncategorized and tagged , , , , , , , . Bookmark the permalink.