点评详情
发布于:2019-7-22 03:49:25  访问:1 次 回复:0 篇
版主管理 | 推荐 | 删除 | 删除并扣分
br General mechanism of NHEJ NHEJ is an amazingly versatile
A number of factors have been shown to remove blocking end groups in order to make the termini of DSBs ligatable. A common non-ligatable end is one that contains either a 3′ phosphate or 5′ hydroxyl. The polynucleotide kinase/phosphatase (PNKP) is the NHEJ processing enzyme responsible for removing 3′ phosphate and 5′ hydroxyl groups and restoring the ligatable 3′ hydroxyl and 5′ phosphate groups. PNKP performs this function via its 5′ kinase and 3′ phosphatase activities [127]. The removal of adenylate groups covalently linked to 5′ phosphate termini are removed by Apratxin, which is a member of the histidine triad family of nucleotide hydrolases and transferases [128]. A surprising discovery was that Ku is able to excise abasic sites near the DSB via an intrinsic 5′deoxyribose-5-phosphate (5′-dRP)/AP lyase activity [129]. Abasic sites within a short 5′ overhang at the DSB end were found to be removed best by Ku.


XRCC4, Ibandronate sodium IV, and XLF
The final step in the repair of a DSB via NHEJ is ligation of the broken ends, which is mediated by DNA ligase IV. DNA ligase IV has activity on its own, but its activity is stimulated by XRCC4 via the ability of XRCC4 to stabilize DNA ligase IV and promote its adenylation [130]. DNA ligase IV is a flexible ligase that can ligate incompatible DNA ends and ligate across gaps [131]. XLF facilitates the ability of DNA ligase IV to ligate mismatched and non-cohesive ends and primes DNA ligase IV for its next catalytic activity by promoting its readenylation [132], [133], [134], [135]. Recently, it was shown that APLF stimulates ligation by XRCC4–DNA ligase IV above that observed in the presence of only Ku70/80 [136]. APLF also was shown to play a role in assembly of the NHEJ complex and that its main function, in conjunction with PARP3, may be to promote the retention of XRCC4, DNA ligase IV, and XLF at DSBs and promoting faster ligation [136], [137].
The versatility of the NHEJ pathway and its factors has been greatly supported by the recent reports that show that XRCC4, DNA ligase IV, and XLF have functions that appear to be independent of the terminal ligation step of the pathway. Interestingly, DNA bound Ku70/80 may not be the only NHEJ protein mediating recruitment of the NHEJ machinery to the DNA damage site as XRCC4 assists in the recruitment of the NHEJ-dependent DNA end processing enzymes to DSBs and may play a role in the ability of the NHEJ complex to choose the correct enzymes to aid in the repair of a specific break. XRCC4 interacts alone or in conjunction with Ku70/80 with the following DNA end processing enzymes, DNA ligase IV, DNA polymerase μ [138], WRN [117], [119], [139], PNKP [140], aprataxin [141], and APLF [120], [142], [143]. Furthermore, XRCC4 may also function in bridging DNA ends. XRCC4 directly interacts with the globular head domain of XLF, creating a head to head interface between the two proteins and structural analysis found that XRCC4 and XLF form super helical filaments via alternating XRCC4 and XLF head domain interfaces which are able to interact with DNA and bridge broken DNA strands [144], [145], [146], [147]. But, it should be noted that the relevance of the XRCC4-XLF multimers in vivo is still under debate as addition of the catalytic domain of DNA ligase IV destabilizes the XRCC4-XLF multimeric complex [148]. However, in human cells XRCC4 is in approximately six-fold excess relative to DNA ligase IV suggesting that XRCC4 likely exists in complexes independently of DNA ligase IV in vivo [149]. Finally, it has been reported that the ligation complex exhibits a non-catalytic function in NHEJ by promoting DNA-PKcs-mediated DNA end synapsis and DNA-PKcs autophosphorylation [26]. This data suggests that a productive NHEJ supramolecular complex consisting of all the canonical NHEJ factors may be responsible for protecting DNA ends.


Conclusions


Conflict of interest
共0篇回复 每页10篇 页次:1/1
共0篇回复 每页10篇 页次:1/1
我要回复
回复内容
验 证 码
看不清?更换一张
匿名发表 
当前位置
脚注信息
版权所有 Copyright(C)2009-2017 北京众康中医养生堂专业调理