A potential link between alternative splicing of the NBS1 gene and DNA damage/environmental stress.
NBS1 forms a multimetric complex with MRE11/RAD50, which acts as the sensor of DNA double-strand breaks (DSBs). The mechanisms controlling the expression of NBS1 remain largely unknown. Here we show that NBS1 is transcribed as both a wild-type and an alternatively spliced form exhibiting a premature stop codon in an alternative 50-bp exon in intron 2. Although the wild-type transcript predominates in most tissues, the spliced transcript is abundant in resting peripheral blood mononuclear cells (PBMCs). Levels of the spliced form of NBS1 decreased rapidly after irradiation as levels of the wild-type NBS1 transcript increased, resulting in increased levels of NBS1 protein. Both mitogenic stimulation and methyl methanesulfonate treatment also altered the splicing pattern of NBS1. Resting PBMCs, which predominantly express spliced NBS1, were more susceptible to radiation than mitogen-stimulated cells, which showed predominant expression of the wild-type transcript. Since the alternatively spliced NBS1 gene likely did not produce protein, this alternative splicing seems to be associated with the control of NBS1 protein. Thus alternative splicing of the NBS1 gene may be associated with the regulation of NBS1 in response to DSBs, DNA alkylation damage, and mitogenic response.
Takai
Ken
K
Laboratory of Virus Control, Institute for Virus Research, Kyoto University, 53 Shogoin Kawara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
Sakamoto
Shuichi
S
Sakai
Tatsunori
T
Yasunaga
Jun-ichirou
J
Komatsu
Kenshi
K
Matsuoka
Masao
M
D017398:Alternative Splicing / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D004249:DNA Damage / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D008934:Mitogens / Q000494:pharmacology; D008969:Molecular Sequence Data; D009153:Mutagens / Q000494:pharmacology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D009928:Organ Specificity; D011485:Protein Binding; D016415:Sequence Alignment
D018797:Cell Cycle Proteins; D008934:Mitogens; D009153:Mutagens; C112156:NBN protein, human; D009687:Nuclear Proteins