p53 gain-of-function cancer mutants induce genetic instability by inactivating ATM

LETTERS

p53 gain-of-function cancer mutants induce genetic instability by inactivating ATM

Hoseok Song1, Monica Hollstein2,3 and Yang Xu1,4

Tp53 is the most commonly mutated tumour-suppressorgene in human cancers1. In addition to the loss of tumour-suppression function, some missense mutants gain novel oncogenic activities2. To elucidate the nature of the gainof function, we introduced the most common p53 cancer mutations (R248W and R273H) independently into the humanized p53 knock-in (HUPKI) allele in mice. Tumour-suppressor functions of p53 are abolished in p53-mutant mice. Several lines of evidence further indicate gain-of-function of p53 mutants in promoting tumorigenesis. p53R248W mice rapidly succumb to certain types of cancersnot commonly observed in p53/ mice. Interchromosomal translocations, a type of genetic instability rarely observed in p53/ cells, are readily detectable in p53-mutant pre-tumor thymocytes. Although normal in p53/ mouse cells, the G2M checkpoint is impaired in p53-mutant cells after DNA damage. These acquired oncogenic properties of mutant p53 could be explained by the findings that these p53 mutants interact with the nuclease Mre11 and suppress the binding of the Mre11 Rad50NBS1 (MRN) complex to DNA double-stranded breaks (DSBs), leading to impaired Ataxia-telangiectasia mutated (ATM) activation. Therefore, p53 gain-of-function mutants promote tumorigenesis by a novel mechanism involving active disruption of critical DNA damage-response pathways.

The tumour suppressor p53 has critical roles in cell-cycle arrest, apoptosis, cellular senescence and differentiation. As a transcription factor, p53 activates the expression of a large number of checkpoint and apoptotic genes, including Puma, Noxa and p21 (ref. 3). In addition, p53 directly suppresses the expression of numerous genes, such as MAP4 and Nanog4,5.

These functions of p53 contribute to genetic stability in both somatic and embryonic stem cells6.

Somatic p53 mutations occur in about half of all human cancers1.

Most of these mutations are missense mutations within the DNA-binding core domain. p53 mutants are often more stable and correlated with

poor prognosis of the cancer patient2. Among missense mutations, there are hotspot mutations at four codons (175, 248, 249 and 273), which together account for over 25% of all missense mutations identified in human cancers7. Both p53R248W and p53R273H mutations are contact mutations that induce conformational changes and abolish the tumour-suppression activities of p53 (ref. 2).

Several lines of evidence suggest that p53 mutants also gain novel activities...