DNA damage can cause mutations that contribute to cellular transformat
ion and tumorigenesis. The p53 tumor suppressor acts to protect the or
ganism from DNA damage by inducing either G(1) arrest to facilitate DN
A repair or by activating physiological cell death (apoptosis). Consis
tent with this critical function of p53, mice lacking p53 are predispo
sed to developing tumors, particularly lymphoma. The severe combined i
mmune deficiency (scid) locus encodes the catalytic subunit of DNA pro
tein kinase (DNA-PKcs), a protein complex that has a role in the cellu
lar response to DNA damage. Cells from scid mice are hypersensitive to
radiation and scid lymphocytes fail to develop from precursors becaus
e they are unable to properly join DNA-coding ends during antigen rece
ptor gene rearrangement. We examined the combined effect of loss of p5
3 and loss of DNA-PKcs on lymphocyte development and tumorigenesis by
generating p53(-/-) scid mice. Our data demonstrate that loss of p53 p
romotes T-cell development in scid mice but does not noticeably affect
B lymphopoiesis. Moreover, scid cells are able to induce p53 protein
expression and activate G, arrest or apoptosis in response to ionizing
radiation, indicating that DNA-PKcs is not essential for these respon
ses to DNA damage. Furthermore, p53(-/-) scid double mutant mice devel
op lymphoma earlier than p53(-/-) littermates, demonstrating that loss
of these two genes can cooperate in tumorigenesis. Collectively, thes
e results provide evidence for an unsuspected role of p53 as a checkpo
int regulator in early T-cell development and demonstrate that loss of
an additional component of the cellular response to DNA damage can co
operate with loss of p53 in lymphomagenesis.