P53 downregulates the Fanconi anaemia DNA repair pathway.

Sara Jaber,Vincent Lejour,Boris Bardot,Franck Toledo,Eléonore Toufektchan

doi:10.1038/ncomms11091

Abstract

Germline mutations affecting telomere maintenance or DNA repair may, respectively, cause dyskeratosis congenita or Fanconi anaemia, two clinically related bone marrow failure syndromes. Mice expressing p53Δ31, a mutant p53 lacking the C terminus, model dyskeratosis congenita. Accordingly, the increased p53 activity in p53Δ31/Δ31 fibroblasts correlated with a decreased expression of 4 genes implicated in telomere syndromes. Here we show that these cells exhibit decreased mRNA levels for additional genes contributing to telomere metabolism, but also, surprisingly, for 12 genes mutated in Fanconi anaemia. Furthermore, p53Δ31/Δ31 fibroblasts exhibit a reduced capacity to repair DNA interstrand crosslinks, a typical feature of Fanconi anaemia cells. Importantly, the p53-dependent downregulation of Fanc genes is largely conserved in human cells. Defective DNA repair is known to activate p53, but our results indicate that, conversely, an increased p53 activity may attenuate the Fanconi anaemia DNA repair pathway, defining a positive regulatory feedback loop.

Highlights

Germline mutations affecting telomere maintenance or DNA repair may, respectively, cause dyskeratosis congenita or Fanconi anaemia, two clinically related bone marrow failure syndromes
Candidates included genes implicated in telomere syndromes (Acd/Tpp[1], Apollo/Snm1b, C16orf57/Mpn1/Usb[1], Naf[1], Obfc1/Stn[1], Parn and Sbds)[5,6,8,9,10]; genes mutated in diseases not primarily associated with telomere biology but for which telomere dysfunction or dyskeratosis congenita (DC)-like features were reported (Dnmt3b, Fancd[2] and Recql4)[6]; genes encoding proteins of complexes involved in telomere biology, that is, the telomerase (Gar1/Nola[1], Ruvbl[1] and Ruvbl2), shelterin (Pot1a and Pot1b, Rap1/Terf2ip, and Terf2), CST (Ten1)
For a gene to be a good candidate, we considered that the mean of its messenger RNA (mRNA) levels in unstressed WT cells should fall between the means measured in p53 À / À and p53D31/D31 cells; and that the means for the three genotypes should be statistically different according to an analysis of variance

Summary

Introduction

Germline mutations affecting telomere maintenance or DNA repair may, respectively, cause dyskeratosis congenita or Fanconi anaemia, two clinically related bone marrow failure syndromes. Loss of the p53 C terminus increases p53 activity in mouse embryonic fibroblasts (MEFs) and in most tested tissues[2,3], and p53D31/D31 MEFs exhibited decreased messenger RNA (mRNA) levels for 4 out of 10 genes implicated in telomere syndromes (Dkc[1], Rtel[1], Tinf[2] and Terf[1]). We tested whether p53 affects the expression of 42 additional genes implicated in telomere metabolism, and found 7 genes that are downregulated in p53D31/D31 cells Some of these p53-regulated genes are involved in the FA DNA repair pathway. These data reveal an unexpected role for p53 in downregulating the FA DNA repair pathway, which may help to understand the pathological processes implicated in FA, and suggest therapeutic strategies against tumour cells that retain a functional p53 pathway

Methods

Results

Conclusion