Inactivation of the SR protein splicing factor ASF/SF2 results in genomic instability

被引：638

作者：

Li, XL ^{[1
]}

Manley, JL ^{[1
]}

机构：

[1] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA

来源：

CELL | 2005年 / 122卷 / 03期

关键词：

D O I：

10.1016/j.cell.2005.06.008

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 [生物化学与分子生物学]; 081704 [应用化学];

摘要：

SR proteins constitute a family of pre-mRNA splicing factors now thought to play several roles in mRNA metabolism in metazoan cells. Here we provide evidence that a prototypical SR protein, ASF/SF2, is unexpectedly required for maintenance of genomic stability. We first show that in vivo depletion of ASF/SF2 results in a hypermutation phenotype likely due to DNA rearrangements, reflected in the rapid appearance of DNA double-strand breaks and high-molecular-weight DNA fragments. Analysis of DNA from ASF/ SF2-depleted cells revealed that the nontemplate strand of a transcribed gene was single stranded due to formation of an RNA:DNA hybrid, R loop structure. Stable overexpression of RNase H suppressed the DNA-fragmentation and hypermutation phenotypes. Indicative of a direct role, ASF/SF2 prevented R loop formation in a reconstituted in vitro transcription reaction. Our results support a model by which recruitment of ASF/SF2 to nascent transcripts by RNA polymerase 11 prevents formation of mutagenic R loop structures.

引用

页码：365 / 378

页数：14

共 57 条

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