An AT-rich sequence in human common fragile site FRA16D causes fork stalling and chromosome breakage in S-cerevisiae

被引:147
作者
Zhang, Haihua
Freudenreich, Catherine H. [1 ]
机构
[1] Tufts Univ, Dept Biol, Medford, MA 02155 USA
[2] Tufts Univ, Sackler Sch Grad Biomed Sci, Genet Program, Boston, MA 02111 USA
关键词
D O I
10.1016/j.molcel.2007.06.012
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Common fragile sites are regions of human chromosomes prone to breakage. Fragile site FRA16D spans the WWOX/FOR tumor suppressor gene and has been linked to cancer-causing deletions and translocations. Using a genetic assay in yeast, we found that a short AT-rich region (Flexl) within FRA16D increases chromosome fragility, whereas three other sequences within FRA16D do not. To our knowledge, this is the first identification of a sequence element within a common fragile site that increases chromosome fragility. The fragility of Flexl was exacerbated by the absence of Rad52 or the presence of hydroxyurea. Flexl contains a polymorphic AT repeat predicted to form a DNA structure, and two-dimensional gel analysis showed accumulation of stalled replication forks at the Flexl sequence that was dependent on AT length. Our data suggest that the FRA16D Flexl sequence causes increased chromosome breakage by forming secondary structures that stall replication fork progression.
引用
收藏
页码:367 / 379
页数:13
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