PubMed · 7163208
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A Falek, K Kidd, M Schiff, B E Ginsburg, K Sandhoff. 1982. Workshop on Human Behavior Genetics.. https://pubmed.ncbi.nlm.nih.gov/7163208/
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Ribosome heterogeneity has emerged as a regulatory layer in gene expression, yet its biological roles in cancers remain poorly characterized. Here, we identify RPL22L1, a paralog of the ribosomal protein RPL22, as a key modulator of DNA damage response (DDR) in colorectal cancer cells. DNA damage induces RPL22L1 upregulation and ribosomal incorporation, forming RPL22L1-specific ribosomes. Ribosome profiling reveals that RPL22L1-containing ribosomes preferentially translate mRNAs with highly structured 5' untranslated region (5'UTR). In particular, RPL22L1 enhances the translation of ATRX through a cap-independent mechanism. ATRX subsequently recruits DNA-PKcs to DNA damage sites, thereby enhancing the DNA repair capacity. RPL22L1 loss creates exploitable DDR vulnerabilities, sensitizing cancer cells to cisplatin and PARP inhibitors in vitro and in vivo. Collectively, these findings uncover a specialized ribosome-mediated translational program in DDR and highlight RPL22L1 as a potential therapeutic target in DDR-based cancer therapy.
Recent molecular epidemiologic research provides compelling new evidence that environmental factors are major contributors to human cancer and that their risks are strongly influenced by genetic and acquired susceptibility. In particular, molecular epidemiology has demonstrated substantial variability in biologic response to carcinogens and suggests that certain groups-such as the very young, those with predisposing genetic traits or nutritional deficits, and even certain ethnic groups-are likely to have greater risk from selected exposures than other members of the population. This work implies that major gains in prevention of cancer, which will claim more than 554 000 American lives this year, will necessitate health and regulatory policies that protect these more susceptible groups and individuals from risks of man-made and naturally occurring environmental carcinogens. The specific implication from this research is that, to be effective in prevention, risk assessments developed in support of these policies by regulatory bodies, such as the Environmental Protection Agency, should reflect the available scientific data on individual variability in both exposure and susceptibility.
The post-UV phenotypes conferred by wild-type plasmids R391 and pYD1, which increase UV-induced mutagenesis but sensitise Escherichia coli AB1157 umuC+ uvrB+ to UV, were compared, alone and in combination with that of plasmid pGW16, which sensitises AB1157 to low, but protects against high UV doses. All three plasmids increased UV resistance when present in Shigella sonnei. No plasmid significantly affected the UV sensitivity of E. coli TK501 umuC uvrB, in which pKM101, the parent of pGW16 increases UV resistance up to 1000-fold. Both pYD1 and R391 reduced the UV protective effect of pKM101, and increased UV-sensitisation conferred by pGW16. UV-sensitisation conferred by pYD1 and R391 was additive when the plasmids were together in strain AB1157, and both pKM101 and pGW16 reduced this additive sensitisation.