Identification of UHRF2 as a novel DNA interstrand crosslink sensor protein.
Identification of UHRF2 as a novel DNA interstrand crosslink sensor protein.
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DOI：
10.1371/journal.pgen.1007643
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发表时间：
2018-10
期刊：
影响因子：
4.5
通讯作者：
Cohn MA
中科院分区：
文献类型：
--
作者：
Motnenko A;Liang CC;Yang D;Lopez-Martinez D;Yoshikawa Y;Zhan B;Ward KE;Tian J;Haas W;Spingardi P;Kessler BM;Kriaucionis S;Gygi SP;Cohn MA
范可尼贫血（FA）通路对于修复DNA双螺旋的沃森-克里克链之间的链间交联（ICL）是重要的。修复过程中的初始且重要阶段是ICL的检测。在这里，我们报告的鉴定UHRF 2，一个parasites的UHRF 1，作为ICL传感器蛋白。UHRF 2在其出现的几秒钟内被募集到基因组中的ICL中。我们表明，UHRF 2与UHRF 1合作，以确保招募FANCD 2 ICL。在UHRF 1和UHRF 2之间，以及在UHRF 1和UHRF 2与FANCD 2之间形成直接的蛋白质-蛋白质相互作用。重要的是，我们证明了FANCD 2的基本单泛素化是由UHRF 1/UHRF 2刺激的。刺激是通过FANCD 2在染色质上的保留介导的，允许其被FA核心复合物单泛素化。总之，我们揭示了UHRF 2感应ICL的机制，导致FANCD 2在ICL的募集和保留，进而通过单泛素化促进FANCD 2的激活。范可尼贫血是一种遗传性疾病，患者通常有先天性异常，发展骨髓衰竭，并患有癌症倾向。患者体内的细胞修复一种DNA损伤的能力降低，其中DNA双螺旋的两条链物理连接在一起，这种修复失败被认为是导致疾病的原因。许多蛋白质参与修复健康个体中的这种类型的DNA损伤，通过称为范可尼贫血途径的复杂DNA修复途径。在这里，我们报告在这一途径中的一个新的球员的识别。这种被称为UHRF 2的蛋白质能够感知基因组中的DNA损伤，从而帮助启动损伤的健康修复。除了提高我们对范可尼贫血途径的分子理解外，从长远来看，这一新知识可能对涉及这种类型DNA损伤的病理学的诊断和治疗具有医学意义。
The Fanconi Anemia (FA) pathway is important for repairing interstrand crosslinks (ICLs) between the Watson-Crick strands of the DNA double helix. An initial and essential stage in the repair process is the detection of the ICL. Here, we report the identification of UHRF2, a paralogue of UHRF1, as an ICL sensor protein. UHRF2 is recruited to ICLs in the genome within seconds of their appearance. We show that UHRF2 cooperates with UHRF1, to ensure recruitment of FANCD2 to ICLs. A direct protein-protein interaction is formed between UHRF1 and UHRF2, and between either UHRF1 and UHRF2, and FANCD2. Importantly, we demonstrate that the essential monoubiquitination of FANCD2 is stimulated by UHRF1/UHRF2. The stimulation is mediating by a retention of FANCD2 on chromatin, allowing for its monoubiquitination by the FA core complex. Taken together, we uncover a mechanism of ICL sensing by UHRF2, leading to FANCD2 recruitment and retention at ICLs, in turn facilitating activation of FANCD2 by monoubiquitination. Fanconi Anemia is a genetic disease where patients typically have congenital abnormalities, develop bone marrow failure and suffer from cancer predisposition. The cells in patients have a reduced ability to repair a type of DNA damage where the two strands of the DNA double helix are physically linked together, and this failure in repair is believed to contribute to cause of the disease. Many proteins are involved in repairing this type of DNA damage in healthy individuals, via a complex DNA repair pathway called the Fanconi Anemia pathway. Here, we report the identification of a new player in this pathway. The protein, called UHRF2, is able to sense the DNA damage in the genome, and thereby help to initiate the healthy repair of the damage. In addition to improving our molecular understanding of the Fanconi Anemia pathway, in the long term, this new knowledge could have medical implications for diagnosis and therapy relating to pathologies involving this type of DNA damage.
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影响因子：
16.6
作者：
Liang CC;Li Z;Lopez-Martinez D;Nicholson WV;Vénien-Bryan C;Cohn MA
通讯作者：
Cohn MA
DOI：
10.1186/s41021-016-0037-9
发表时间：
2016
期刊：
Genes and environment : the official journal of the Japanese Environmental Mutagen Society
影响因子：
--
作者：
Hashimoto S;Anai H;Hanada K
通讯作者：
Hanada K
DOI：
10.1007/s00018-016-2218-x
发表时间：
2016-08
期刊：
Cellular and molecular life sciences : CMLS
影响因子：
--
作者：
Lopez-Martinez D;Liang CC;Cohn MA
通讯作者：
Cohn MA
影响因子：
16
作者：
Ciccia, Alberto;Ling, Chen;West, Stephen C.
通讯作者：
West, Stephen C.
影响因子：
4.8
作者：
Bashtrykov, Pavel;Jankevicius, Gytis;Jeltsch, Albert
通讯作者：
Jeltsch, Albert