MUTATIONS IN THE P53 AND SCID GENES COOPERATE IN TUMORIGENESIS

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.