据一篇发表于Science杂志的研究报告，美国洛克菲勒大学和哈佛大学的研究人员发现了在一种致命的DNA损伤中起重要修复作用的两种蛋白质——FANCI和FANCD2。
据研究人员Agata Smogorzewska介绍，DNA内部链交联(inter-strand crosslinks)是DNA双螺旋链内部发生交联引起的严重的DNA损伤，能够阻断DNA的复制和转录。在人体的每个细胞内，每天大约发生10次左右的内部链交联。研究人员怀疑这两种蛋白质可直接参与到DNA的修复过程中，虽然研究人员知道这两种蛋白会出现在DNA的损伤位点，但这两种蛋白质的功能却一直是个谜。
FANCI和FANCD2蛋白是Fanconi贫血通路中的两种蛋白质，这两种蛋白质可修复DNA内部链交联。如果参与该通路的13种蛋白质中任何一个发生损伤，将引起Fanconi贫血症——一种导致骨髓衰竭、白血病以及多种生理缺陷的血液疾病。
在2007年，Smogorzewska发现FANCI蛋白与FANCD2蛋白可形成复合体，该复合体经过泛素化(ubiquitylation)修饰后，被招募到发生DNA链交联的位点，与其它分子共同完成修复过程。此前，研究人员虽然知道DNA的修复过程包括了损伤DNA的修剪和更换，但研究人员不清楚FANCI和FANCD2是否参与了分子修剪过程。
通过使用青蛙卵提取物建立的特殊细胞系统，研究人员发现这两种蛋白质在DNA的切除和插入步骤中十分关键，这有力地证明了Fanconi贫血症实际上是一种DNA修复障碍病。这项发现还解释了Fanconi贫血症患者中提取的细胞经过内部链交联诱导药物的处理后，细胞会发生死亡的原因。（生物谷Bioon.com）
生物谷推荐原始出处：
Science 18 December 2009: DOI: 10.1126/science.1182372
The Fanconi Anemia Pathway Promotes Replication-Dependent DNA Interstrand Cross-Link Repair
Puck Knipscheer,1 Markus R?schle,2 Agata Smogorzewska,3,4,* Milica Enoiu,5 The Vinh Ho,6 Orlando D. Sch?rer,5,6 Stephen J. Elledge,3 Johannes C. Walter1,
Fanconi anemia is a human cancer predisposition syndrome caused by mutations in 13 Fanc genes. The disorder is characterized by genomic instability and cellular hypersensitivity to chemicals that generate DNA interstrand cross-links (ICLs). A central event in the activation of the Fanconi anemia pathway is the mono-ubiquitylation of the FANCI-FANCD2 complex, but how this complex confers ICL resistance remains enigmatic. Using a cell-free system, we showed that FANCI-FANCD2 is required for replication-coupled ICL repair in S phase. Removal of FANCD2 from extracts inhibits both nucleolytic incisions near the ICL and translesion DNA synthesis past the lesion. Reversal of these defects requires ubiquitylated FANCI-FANCD2. Our results show that multiple steps of the essential S-phase ICL repair mechanism fail when the Fanconi anemia pathway is compromised.
1 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
2 Department of Molecular Cell Biology, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
3 Department of Genetics, Harvard Medical School, and Division of Genetics, Brigham and Women’s Hospital, Boston, MA 02115, USA.
4 Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
5 Institute of Molecular Cancer Research, University of Zurich, 8057 Zurich, Switzerland.
6 Departments of Pharmacological Sciences and Chemistry, Stony Brook University, Stony Brook, NY 11794, USA.
