p53 genes function to restrain mobile elements

Abstract

Throughout the animal kingdom, p53 genes govern stress response networks by specifying adaptive transcriptional responses. The human member of this gene family is mutated in most cancers, but precisely how p53 functions to mediate tumor suppression is not well understood. Using Drosophila and zebrafish models, we show that p53 restricts retrotransposon activity and genetically interacts with components of the piRNA (piwi-interacting RNA) pathway. Furthermore, transposon eruptions occurring in the p53 − germline were incited by meiotic recombination, and transcripts produced from these mobile elements accumulated in the germ plasm. In gene complementation studies, normal human p53 alleles suppressed transposons, but mutant p53 alleles from cancer patients could not. Consistent with these observations, we also found patterns of unrestrained retrotransposons in p53-driven mouse and human cancers. Furthermore, p53 status correlated with repressive chromatin marks in the 5 ′ sequence of a synthetic LINE-1 element. Together, these observations indicate that ancestral functions of p53 operate through conserved mechanisms to contain retrotransposons. Since human p53 mutants are disabled for this activity, our findings raise the possibility that p53 mitigates oncogenic disease in part by restricting transposon mobility.

L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis

“…To our knowledge, this is the first report of endogenous L1 mobilization being observed directly in a nonhuman cancer, with the possible exception of an L1 mutation found proximal to MYC in canine transmissible venereal tumors and arising either in the dog germline or the somatic evolution of the original tumor (Murgia et al 2006). Combined with a previous report of L1 and IAP protein expression in tumors obtained from a Myc murine liver cancer model (Wylie et al 2016), our results highlight mouse as a suitable system to study L1 activity in oncogenesis and cancer progression, which may be useful for future studies that are not feasible using human patient samples. Indeed, the finding that Mdr2 −/− mice accommodate tumor-specific L1 retrotransposition is particularly interesting, as these genomic alterations occur alongside massive gene amplifications (Iannelli et al 2014).…”

Diverse repetitive element RNA expression defines epigenetic and immunologic features of colon cancer

“…Recently, a variety of repeat RNAs have been shown to activate the innate immune response through the pattern recognition receptor pathways (8,9,14,15). The expression of these repeats appears to be a combination of p53 function and DNA CpG methylation in model organisms (14,16). Our results have defined these Node, lymph node metastasis; +/-, node with or without metastasis.…”

Putting p53 in Context

“…However, recent evidence demonstrates that the association between p53 mutation and retrotransposon expression is more than simply a culling effect: indeed, p53 binding to target sites within LINE elements and other transposon sequences are associated with their downregulation (Chang et al, 2007). p53-mediated repression is dependent on epigenetic silencing of retrotransposon loci and not apoptosis, and derepressed retrotransposons are competent for reintegration into the genome (Leonova et al, 2013; Wylie et al, 2016), promoting mutagenesis (Tubio et al, 2014). Genomic analyses have revealed that retrotransposon mobilization is common in human cancers (Ting et al, 2011; Tubio et al, 2014).…”

“…Genomic analyses have revealed that retrotransposon mobilization is common in human cancers (Ting et al, 2011; Tubio et al, 2014). While the precise impact remains to be determined, there is a significant association between repetitive element expression and p53 status in mouse and human tumors (Wylie et al., 2016). …”