據(jù)一篇發(fā)表于Science雜志的研究報(bào)告，美國(guó)洛克菲勒大學(xué)和哈佛大學(xué)的研究人員發(fā)現(xiàn)了在一種致命的DNA損傷中起重要修復(fù)作用的兩種蛋白質(zhì)——FANCI和FANCD2,。
據(jù)研究人員Agata Smogorzewska介紹，DNA內(nèi)部鏈交聯(lián)(inter-strand crosslinks)是DNA雙螺旋鏈內(nèi)部發(fā)生交聯(lián)引起的嚴(yán)重的DNA損傷,，能夠阻斷DNA的復(fù)制和轉(zhuǎn)錄,。在人體的每個(gè)細(xì)胞內(nèi)，每天大約發(fā)生10次左右的內(nèi)部鏈交聯(lián),。研究人員懷疑這兩種蛋白質(zhì)可直接參與到DNA的修復(fù)過(guò)程中,，雖然研究人員知道這兩種蛋白會(huì)出現(xiàn)在DNA的損傷位點(diǎn)，但這兩種蛋白質(zhì)的功能卻一直是個(gè)謎,。
FANCI和FANCD2蛋白是Fanconi貧血通路中的兩種蛋白質(zhì),，這兩種蛋白質(zhì)可修復(fù)DNA內(nèi)部鏈交聯(lián)。如果參與該通路的13種蛋白質(zhì)中任何一個(gè)發(fā)生損傷,，將引起Fanconi貧血癥——一種導(dǎo)致骨髓衰竭,、白血病以及多種生理缺陷的血液疾病。
在2007年,，Smogorzewska發(fā)現(xiàn)FANCI蛋白與FANCD2蛋白可形成復(fù)合體,，該復(fù)合體經(jīng)過(guò)泛素化(ubiquitylation)修飾后，被招募到發(fā)生DNA鏈交聯(lián)的位點(diǎn),，與其它分子共同完成修復(fù)過(guò)程,。此前，研究人員雖然知道DNA的修復(fù)過(guò)程包括了損傷DNA的修剪和更換,，但研究人員不清楚FANCI和FANCD2是否參與了分子修剪過(guò)程,。
通過(guò)使用青蛙卵提取物建立的特殊細(xì)胞系統(tǒng)，研究人員發(fā)現(xiàn)這兩種蛋白質(zhì)在DNA的切除和插入步驟中十分關(guān)鍵,，這有力地證明了Fanconi貧血癥實(shí)際上是一種DNA修復(fù)障礙病。這項(xiàng)發(fā)現(xiàn)還解釋了Fanconi貧血癥患者中提取的細(xì)胞經(jīng)過(guò)內(nèi)部鏈交聯(lián)誘導(dǎo)藥物的處理后,，細(xì)胞會(huì)發(fā)生死亡的原因,。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
