Regulation of ceramide synthase-mediated crypt epithelium apoptosis by DNA damage repair enzymes Journal Article
| Authors: | Rotolo, J. A.; Mesicek, J.; Maj, J.; Truman, J. P.; Haimovitz-Friedman, A.; Kolesnick, R.; Fuks, Z. |
| Article Title: | Regulation of ceramide synthase-mediated crypt epithelium apoptosis by DNA damage repair enzymes |
| Abstract: | Acute endothelial cell apoptosis and microvascular compromise couple gastrointestinal tract irradiation to reproductive death of intestinal crypt stem cell clonogens (SCCs) following high-dose radiation. Genetic or pharmacologic inhibition of endothelial apoptosis prevents intestinal damage, but as the radiation dose is escalated, SCCs become directly susceptible to an alternate cell death mechanism, mediated via ceramide synthase (CS)-stimulated de novo synthesis of the proapoptotic sphingolipid ceramide, and p53-independent apoptosis of crypt SCCs. We previously reported that ataxia-telangiectasia mutated deficiency resets the primary radiation lethal pathway, allowing CS-mediated apoptosis at the low-dose range of radiation. The mechanism for this event, termed target reordering, remains unknown. Here, we show that inactivation of DNA damage repair pathways signals CS-mediated apoptosis in crypt SCCs, presumably via persistent unrepaired DNA double-strand breaks (DSBs). Genetic loss of function of sensors and transducers of DNA DSB repair confers the CS-mediated lethal pathway in intestines of sv129/B6Mre11 ATLD1/ATLD1 and C57BL/ 6Prkdc/SCID (severe combined immunodeficient) mice exposed to low-dose radiation. In contrast, CS-mediated SCC lethality was mitigated in irradiated gain-of-function Rad50s/s mice, and epistasis studies order Rad50 upstream of Mre11. These studies suggest unrepaired DNA DSBs as causative in target reordering in intestinal SCCs. As such, we provide an in vivo model of DNA damage repair that is standardized, can be exploited to understand allele-specific regulation in intact tissue, and is pharmacologically tractable. ©2010 AACR. |
| Keywords: | controlled study; dna-binding proteins; nonhuman; radiation dose; animal cell; mouse; animals; cell cycle proteins; mice; mice, knockout; animal tissue; dna damage; atp-binding cassette transporters; dna repair; apoptosis; animal experiment; animal model; mice, scid; mice, inbred c57bl; radiation exposure; dna strand breakage; mice, inbred strains; double stranded dna; protein-serine-threonine kinases; tumor suppressor proteins; atm protein; dna breaks, double-stranded; dna repair enzymes; stem cells; protein deficiency; epithelium; oxidoreductases; loss of function mutation; low energy radiation; intestine; jejunum; clonogenesis; ceramides; sphingosine acyltransferase; transducer; intestinal mucosa; epistasis; recombinant basic fibroblast growth factor; crypt cell |
| Journal Title: | Cancer Research |
| Volume: | 70 |
| Issue: | 3 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2010-02-01 |
| Start Page: | 957 |
| End Page: | 967 |
| Language: | English |
| DOI: | 10.1158/0008-5472.can-09-1562 |
| PUBMED: | 20086180 |
| PROVIDER: | scopus |
| PMCID: | PMC4440583 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 1" - "Export Date: 20 April 2011" - "CODEN: CNREA" - "Source: Scopus" |
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