Human HMGB1 directly facilitates interactions between nucleotide excision repair proteins on triplex-directed psoralen interstrand crosslinks.
Human HMGB1 directly facilitates interactions between nucleotide excision repair proteins on triplex-directed psoralen interstrand crosslinks.
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DOI：
10.1016/j.dnarep.2009.04.001
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发表时间：
2009-07-04
期刊：
影响因子：
3.8
通讯作者：
Vasquez KM
中科院分区：
文献类型：
--
作者：
Lange SS;Reddy MC;Vasquez KM
Pceptien是一种通过产生DNA链间交联（ICL）起作用的化疗剂，其特别具有细胞毒性和致突变性，因为其复杂的化学性质使其难以修复。来自多个修复途径的蛋白质，包括核苷酸切除修复（NER），参与了哺乳动物细胞中它们的去除，但对其修复的确切性质知之甚少。我们以前已经表明，HMGB 1，一种参与染色质结构，转录调控和炎症的蛋白质，可以与RPA协同结合到三链体定向的peptide ICL，并且缺乏HMGB 1的哺乳动物细胞对peptide ICL超敏感。然而，这种效应是否是由HMGB 1在DNA损伤识别中的作用介导的仍然是未知的。鉴于HMGB 1与受损DNA结合的能力及其与RPA蛋白的相互作用，我们假设HMGB 1与NER损伤识别蛋白一起工作，以帮助清除ICL。我们在这里表明，HMGB 1能够结合到三链体定向peptide ICL与专用NER损伤识别复合物XPC-RAD 23 B，以及RPA，并且它们在这些病变上形成高分子量复合物。此外，我们证明了HMGB 1与XPC-RAD 23 B和XPA在没有DNA的情况下相互作用。这些发现直接证明了HMGB 1和NER损伤识别蛋白之间的相互作用，并表明HMGB 1可能通过增强NER损伤识别因子之间的相互作用来影响ICL修复。
Psoralen is a chemotherapeutic agent that acts by producing DNA interstrand crosslinks (ICLs), which are especially cytotoxic and mutagenic because their complex chemical nature makes them difficult to repair. Proteins from multiple repair pathways, including nucleotide excision repair (NER), are involved in their removal in mammalian cells, but the exact nature of their repair is poorly understood. We have shown previously that HMGB1, a protein involved in chromatin structure, transcriptional regulation, and inflammation, can bind cooperatively to triplex-directed psoralen ICLs with RPA, and that mammalian cells lacking HMGB1 are hyper-sensitive to psoralen ICLs. However, whether this effect is mediated by a role for HMGB1 in DNA damage recognition is still unknown. Given HMGB1’s ability to bind to damaged DNA and its interaction with the RPA protein, we hypothesized that HMGB1 works together with the NER damage recognition proteins to aid in the removal of ICLs. We show here that HMGB1 is capable of binding to triplex-directed psoralen ICLs with the dedicated NER damage recognition complex XPC-RAD23B, as well as RPA, and that they form a high molecular weight complex on these lesions. In addition, we demonstrate that HMGB1 interacts with XPC-RAD23B and XPA in the absence of DNA. These findings directly demonstrate interactions between HMGB1 and the NER damage recognition proteins, and suggest that HMGB1 may affect ICL repair by enhancing the interactions between NER damage recognition factors.
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