Interplay of p53 and DNA-repair protein XRCC4 in tumorigenesis, genomic stability and development

Yijie Gao, David O. Ferguson, Wei Xie, John P. Manis, JoAnn Sekiguchi, Karen M. Frank, Jayanta Chaudhuri, James Horner, Ronald A. DePinho and Frederick W. Alt ()
Additional contact information
Yijie Gao: Howard Hughes Medical Institute, The Children's Hospital, and Centre for Blood Research
David O. Ferguson: Howard Hughes Medical Institute, The Children's Hospital, and Centre for Blood Research
Wei Xie: Howard Hughes Medical Institute, The Children's Hospital, and Centre for Blood Research
John P. Manis: Howard Hughes Medical Institute, The Children's Hospital, and Centre for Blood Research
JoAnn Sekiguchi: Howard Hughes Medical Institute, The Children's Hospital, and Centre for Blood Research
Karen M. Frank: Howard Hughes Medical Institute, The Children's Hospital, and Centre for Blood Research
Jayanta Chaudhuri: Howard Hughes Medical Institute, The Children's Hospital, and Centre for Blood Research
James Horner: Medicine and Genetics, Harvard Medical School and Dana Farber Cancer Institute
Ronald A. DePinho: Medicine and Genetics, Harvard Medical School and Dana Farber Cancer Institute
Frederick W. Alt: Howard Hughes Medical Institute, The Children's Hospital, and Centre for Blood Research

Nature, 2000, vol. 404, issue 6780, 897-900

Abstract: Abstract XRCC4 is a non-homologous end-joining protein employed in DNA double strand break repair and in V(D)J recombination1,2. In mice, XRCC4-deficiency causes a pleiotropic phenotype, which includes embryonic lethality and massive neuronal apoptosis2. When DNA damage is not repaired, activation of the cell cycle checkpoint protein p53 can lead to apoptosis3. Here we show that p53-deficiency rescues several aspects of the XRCC4-deficient phenotype, including embryonic lethality, neuronal apoptosis, and impaired cellular proliferation. However, there was no significant rescue of impaired V(D)J recombination or lymphocyte development. Although p53-deficiency allowed postnatal survival of XRCC4-deficient mice, they routinely succumbed to pro-B-cell lymphomas which had chromosomal translocations linking amplified c-myc oncogene and IgH locus sequences. Moreover, even XRCC4-deficient embryonic fibroblasts exhibited marked genomic instability including chromosomal translocations. Our findings support a crucial role for the non-homologous end-joining pathway as a caretaker of the mammalian genome, a role required both for normal development and for suppression of tumours.

Date: 2000
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/35009138 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:404:y:2000:i:6780:d:10.1038_35009138

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/35009138

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().