An MLH1 mutation links BACH1/FANCJ to colon cancer, signaling, and insight toward directed therapy.
An MLH1 mutation links BACH1/FANCJ to colon cancer, signaling, and insight toward directed therapy.
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DOI：
10.1158/1940-6207.capr-10-0118
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发表时间：
2010-11
期刊：
影响因子：
--
通讯作者：
Cantor SB
中科院分区：
文献类型：
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作者：
Xie J;Guillemette S;Peng M;Gilbert C;Buermeyer A;Cantor SB
MLH 1的缺陷，与其他错配修复（MMR）蛋白一样，是遗传性非息肉病性结肠癌（HNPCC）的主要原因。MMR基因突变通常会破坏错配修复和MMR信号传导功能。然而，一些HNPC相关突变的致病性尚不清楚。在这里，我们发现MLH 1临床突变与亮氨酸（L）到组氨酸（H）的氨基酸变化在位置607，消融MLH 1结合FANCJ。鉴于DNA解旋酶在体外对哺乳动物MMR不是必需的，我们认为MLH 1与FANCJ结合的丧失可能改变MMR信号传导。与这一假设相一致，FANCJ缺陷细胞表现出延迟的MMR信号传导和凋亡反应，从而对诱导O 6-甲基鸟嘌呤病变的药物产生抗性。我们的数据表明，MMR信号的延迟为甲基鸟嘌呤甲基转移酶（MGMT）逆转DNA甲基化提供了时间。从本质上讲，FANCJ缺陷改变了两种途径之间的竞争：MGMT-prosurvival与MMR-prodeath。这一结果可以解释HNPCC家族性癌症表现为微卫星稳定和完整的MMR，如MLHL 607 H。重要的是，FANCJ和HNPCC之间的联系提供了对定向治疗的见解，因为FANCJ/MLH 1相互作用的丧失也独特地使细胞对DNA交联剂敏感。
Defects in MLH1, as with other mismatch repair (MMR) proteins, are the primary cause of hereditary nonpolyposis colon cancer (HNPCC). Mutations in MMR genes often disrupt mismatch repair and MMR signaling functions. However, some HNPCC-associated mutations have unknown pathogenicity. Here, we uncover an MLH1 clinical mutation with a leucine (L)-to-histidine (H) amino acid change at position 607 that ablates MLH1 binding to FANCJ. Given that a DNA helicase is not essential for mammalian MMR in vitro, we considered that loss of MLH1 binding to FANCJ could alter MMR signaling. Consistent with this hypothesis, FANCJ-deficient cells exhibit delayed MMR signaling and apoptotic responses that generate resistance to agents that induce O6-methylguanine lesions. Our data indicate that the delay in MMR signaling provides time for the methylguanine methyltransferase (MGMT) enzyme to reverse DNA methylation. In essence, FANCJ deficiency alters the competition between two pathways: MGMT-prosurvival versus MMR-prodeath. This outcome could explain the HNPCC familial cancers that present as microsatellite stable and with intact MMR, such as MLHL607H. Importantly, the link between FANCJ and HNPCC provides insight toward directed therapies because loss of the FANCJ/MLH1 interaction also uniquely sensitizes cells to DNA cross-linking agents.