Pot1 OB-fold mutations unleash telomere instability to initiate tumorigenesis.
Pot1 OB-fold mutations unleash telomere instability to initiate tumorigenesis.
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DOI：
10.1038/onc.2016.405
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发表时间：
2017-04-06
期刊：
影响因子：
8
通讯作者：
Chang S
中科院分区：
文献类型：
--
作者：
Gu P;Wang Y;Bisht KK;Wu L;Kukova L;Smith EM;Xiao Y;Bailey SM;Lei M;Nandakumar J;Chang S
染色体畸变是人类癌症的标志，复杂的细胞遗传学重排导致允许癌症发生和发展的遗传变化。端粒保护蛋白1（POT 1）是shelterin复合物的重要组成部分，通过抑制端粒处异常DNA损伤和修复反应的激活来维持染色体稳定性。POT 1的寡糖-寡核苷酸（OB）折叠中的零星和家族性突变已在许多人类癌症中被鉴定，但hPOT 1突变如何启动肿瘤发生的潜在机制仍不清楚。在这里，我们表明，人类POT 1的OB折叠是必不可少的保护新复制的端粒。hPOT 1 OB-折叠中的致癌突变不能与ss端粒DNA结合，引发端粒处的DNA损伤反应，通过诱变替代非同源末端连接（A-NHEJ）途径促进不适当的染色体融合。hPOT 1突变也导致端粒延长和可移植造血系统恶性肿瘤的形成。引人注目的是，在小鼠乳腺上皮细胞中的mPot 1a和p53的条件性缺失导致高度侵袭性乳腺癌的发展，并形成含有大量端粒融合阵列的整个染色体，让人联想到chromothripsis。我们的研究结果表明，hPOT 1 OB-folds需要保护和防止新复制的端粒参与A-NHEJ介导的融合，否则将促进基因组不稳定性，以燃料肿瘤发生。
Chromosomal aberrations are a hallmark of human cancers, with complex cytogenetic rearrangements leading to genetic changes permissive for cancer initiation and progression. Protection of Telomere 1 (POT1) is an essential component of the shelterin complex and functions to maintain chromosome stability by repressing the activation of aberrant DNA damage and repair responses at telomeres. Sporadic and familial mutations in the oligosaccharide-oligonucleotide (OB) folds of POT1 have been identified in many human cancers, but the mechanism underlying how hPOT1 mutations initiate tumorigenesis has remained unclear. Here we show that the human POT1’s OB-folds are essential for the protection of newly replicated telomeres. Oncogenic mutations in hPOT1 OB-fold fail to bind to ss telomeric DNA, eliciting a DNA damage response at telomeres that promote inappropriate chromosome fusions via the mutagenic alternative non-homologous end joining (A-NHEJ) pathway. hPOT1 mutations also result in telomere elongation and the formation of transplantable hematopoietic malignancies. Strikingly, conditional deletion of both mPot1a and p53 in mouse mammary epithelium resulted in development of highly invasive breast carcinomas and the formation of whole chromosomes containing massive arrays of telomeric fusions reminiscent of chromothripsis. Our results reveal that hPOT1 OB-folds are required to protect and prevent newly replicated telomeres from engaging in A-NHEJ mediated fusions that would otherwise promote genome instability to fuel tumorigenesis.