RB stabilizes XPC and promotes cellular NER.

It has long been thought that the G(1)/S cell cycle checkpoint allows time for DNA repair by delaying S-phase entry. The p53 tumor suppressor pathway regulates the G(1)/S checkpoint by regulating the cyclin-dependent kinase inhibitor p21(Waf1/Cip1), but p53 also regulates the nucleotide excision DNA repair protein XPC. Here, using p53-null cell lines we show that additional mechanisms stabilize XPC protein and promote nucleotide excision repair (NER) in concert with the G(1)/S checkpoint. At least one mechanism to stabilize and destabilize XPC involves ubiquitin-mediated degradation of XPC, as the ubiquitin ligase inhibitor MG-132 blocked XPC degradation. The retinoblastoma protein RB, in its unphosphorylated form actually stabilized XPC and promoted NER as measured by host cell reactivation experiments. The data suggest that XPC protein and XPC-mediated NER are tightly linked to the G(1)/S checkpoint, even in cells lacking functional p53.

Selenomethionine or methylseleninic acid inhibits mutagenesis of a reporter gene in mouse bone marrow.

Recent laboratory and clinical studies have utilized selenium in the form of pure seleno-L-methionine (SeMet) in combination with DNA-damaging cancer chemotherapy drugs. In mice, the selenium protected bone marrow and other tissues from dose-limiting toxicity. In fact, because of the protection from dose-limiting toxicity, a doubling or even tripling of the maximum tolerated dose (MTD) was enabled. Previously we showed that SeMet protects bone marrow by a DNA repair mechanism that requires the XPC DNA repair protein. XPC is rate-limiting and is required for repair of cisplatin or carboplatin adducts. Herein we used a mouse strain that carries a lambda phage reporter gene in the genome that serves as a mutagenesis target. SeMet protects from carboplatin mutagenesis in mouse bone marrow. Methylseleninic acid (MSA), a metabolite of SeMet, also protected against mutagenesis in mouse bone marrow.