Adams Melissa M, Wang Bin, Xia Zhenfang, Morales Julio C, Lu Xiongbin, Donehower Lawrence A, Bochar Daniel A, Elledge Stephen J, Carpenter Phillip B
Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, Texas 77030, USA.
Cell Cycle. 2005 Dec;4(12):1854-61. doi: 10.4161/cc.4.12.2282. Epub 2005 Dec 28.
p53 binding protein 1 (53BP1) participates in the repair of DNA double stranded breaks (DSBs) where it is recruited to or near sites of DNA damage. Although little is known about the biochemical functions of 53BP1, the protein possesses several motifs that are likely important for its role as a DNA damage response element. This includes two BRCA1 C-terminal repeats, tandem Tudor domains, and a variety of phosphorylation sites. Here we show that a glycine-arginine rich (GAR) stretch of 53BP1 lying upstream of the Tudor motifs is methylated. We demonstrate that arginine residues within this region are important for asymmetric methylation by the PRMT1 methyltransferase. We further show that sequences upstream of the Tudor domains that do not include the GAR stretch are sufficient for 53BP1 oligomerization in vivo. Thus, although Tudor domains bind methylated proteins, 53BP1 homo-oligomerization occurs independently of Tudor function. Lastly, we find that deficiencies in 53BP1 generate a "hyper-rec" phenotype. Collectively, these data provide new insight into 53BP1, an important component in maintaining genomic stability.
p53结合蛋白1（53BP1）参与DNA双链断裂（DSB）的修复，它被招募到DNA损伤位点或其附近。尽管对53BP1的生化功能了解甚少，但该蛋白具有几个基序，这些基序可能对其作为DNA损伤反应元件的作用很重要。这包括两个BRCA1 C末端重复序列、串联的Tudor结构域以及各种磷酸化位点。在这里，我们表明位于Tudor基序上游的53BP1富含甘氨酸-精氨酸（GAR）的区域发生了甲基化。我们证明该区域内的精氨酸残基对于PRMT1甲基转移酶的不对称甲基化很重要。我们进一步表明，Tudor结构域上游不包括GAR区域的序列足以在体内实现53BP1的寡聚化。因此，尽管Tudor结构域结合甲基化蛋白，但53BP1的同源寡聚化独立于Tudor功能而发生。最后，我们发现53BP1的缺陷会产生“超修复”表型。总的来说，这些数据为53BP1提供了新的见解，53BP1是维持基因组稳定性的重要组成部分。
