Motifs of the C-terminal domain of MCM9 direct localization to sites of mitomycin-C damage for RAD51 recruitment.
Motifs of the C-terminal domain of MCM9 direct localization to sites of mitomycin-C damage for RAD51 recruitment.
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DOI：
10.1016/j.jbc.2021.100355
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Trakselis MA
中科院分区：
文献类型：
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作者：
McKinzey DR;Gomathinayagam S;Griffin WC;Klinzing KN;Jeffries EP;Rajkovic A;Trakselis MA
MCM 8/9复合物涉及响应于几种DNA损伤剂而帮助叉进展和促进同源重组（HR）。MCM 9本身是MCM家族中的一个离群值，含有占总长度42%的长C末端延伸（CTE），但没有已知的功能组分和高度预测的紊乱。在这份报告中，我们确定和表征两个独特的图案内的主要是非结构化的CTE所需的本地化的MCM 8/9的丝裂霉素C（MMC）诱导的DNA损伤的网站。首先，MCM 8和MCM 9的核输入都需要非常规的“二分体样”核定位（NLS）基序，其由两个带正电荷的氨基酸段组成，所述氨基酸段由长的间插序列分开。第二，类似于在其他HR解旋酶中发现的BRC基序（BRCv）的变体对于MMC损伤位点的定位是必要的。MCM 9-BRCv直接与MMC诱导的损伤下游的RAD 51相互作用并将其募集到MMC诱导的损伤下游以帮助DNA修复。缺乏功能性MCM 9和离散MCM 9敲除细胞的患者淋巴细胞在MMC治疗后形成RAD 51病灶的能力显著受损。因此，MCM 9中的无序CTE在促进MCM 8/9活性和招募下游相互作用因子方面具有重要功能;因此，需要全长MCM 9才能进行适当的DNA修复。
The MCM8/9 complex is implicated in aiding fork progression and facilitating homologous recombination (HR) in response to several DNA damage agents. MCM9 itself is an outlier within the MCM family containing a long C-terminal extension (CTE) comprising 42% of the total length, but with no known functional components and high predicted disorder. In this report, we identify and characterize two unique motifs within the primarily unstructured CTE that are required for localization of MCM8/9 to sites of mitomycin C (MMC)-induced DNA damage. First, an unconventional “bipartite-like” nuclear localization (NLS) motif consisting of two positively charged amino acid stretches separated by a long intervening sequence is required for the nuclear import of both MCM8 and MCM9. Second, a variant of the BRC motif (BRCv) similar to that found in other HR helicases is necessary for localization to sites of MMC damage. The MCM9-BRCv directly interacts with and recruits RAD51 downstream to MMC-induced damage to aid in DNA repair. Patient lymphocytes devoid of functional MCM9 and discrete MCM9 knockout cells have a significantly impaired ability to form RAD51 foci after MMC treatment. Therefore, the disordered CTE in MCM9 is functionally important in promoting MCM8/9 activity and in recruiting downstream interactors; thus, requiring full-length MCM9 for proper DNA repair.
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影响因子：
16.8
作者：
Bhat KP;Cortez D
通讯作者：
Cortez D
影响因子：
5.6
作者：
Fontes, MRM;Teh, T;Kobe, B
通讯作者：
Kobe, B
影响因子：
2.9
作者：
EASTMAN, A
通讯作者：
EASTMAN, A
影响因子：
5.8
作者：
Desai, Swapna;Wood-Trageser, Michelle;Rajkovic, Aleksandar
通讯作者：
Rajkovic, Aleksandar
DOI：
10.1038/nrc3088
发表时间：
2011-06-24
期刊：
Nature reviews. Cancer
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