XRCC4 suppresses medulloblastomas with recurrent translocations in p53-deficient mice.
Inactivation of the XRCC4 nonhomologous end-joining factor in the mouse germ line leads to embryonic lethality, in association with apoptosis of newly generated, postmitotic neurons. We now show that conditional inactivation of the XRCC4 in nestin-expressing neuronal progenitor cells, although leading to no obvious phenotype in a WT background, leads to early onset of neuronally differentiated medulloblastomas (MBs) in a p53-deficient background. A substantial proportion of the XRCC4/p53-deficient MBs have high-level N-myc gene amplification, often intrachromosomally in the context of complex translocations or other alterations of chromosome 12, on which N-myc resides, or extrachromosomally within double minutes. In addition, most XRCC4/p53-deficient MBs harbor clonal translocations of chromosome 13, which frequently involve chromosome 6 as a partner. One copy of the patched gene (Ptc), which lies on chromosome 13, was deleted in all tested XRCC4/p53-deficient MBs in the context of translocations or interstitial deletions. In addition, Cyclin D2, a chromosome 6 gene, was amplified in a subset of tumors. Notably, amplification of Myc-family or Cyclin D2 genes and deletion of Ptc also have been observed in human MBs. We therefore conclude that, in neuronal cells of mice, the nonhomologous end-joining pathway plays a critical role in suppressing genomic instability that, in a p53-deficient background, routinely contributes to genesis of MBs with recurrent chromosomal alterations.
Yan
Catherine T
CT
Howard Hughes Medical Institute, The Children's Hospital, CBR Institute for Biomedical Research, Harvard Medical School, Boston, MA 02115, USA.
Kaushal
Dhruv
D
Murphy
Michael
M
Zhang
Yu
Y
Datta
Abhishek
A
Chen
Changzhong
C
Monroe
Brianna
B
Mostoslavsky
Gustavo
G
Coakley
Kristen
K
Gao
Yijie
Y
Mills
Kevin D
KD
Fazeli
Alex P
AP
Tepsuporn
Suprawee
S
Hall
Giles
G
Mulligan
Richard
R
Fox
Edward
E
Bronson
Roderick
R
De Girolami
Umberto
U
Lee
Charles
C
Alt
Frederick W
FW