Alterations of DNA damage-response genes ATM and ATR in pyothorax-associated lymphoma
Alterations of DNA damage-response genes ATM and ATR in pyothorax-associated lymphoma
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DOI：
10.1038/labinvest.3700235
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发表时间：
2005-03-01
影响因子：
5
通讯作者：
Aozasa, K
中科院分区：
文献类型：
--
作者：
Liu, A;Takakuwa, T;Aozasa, K
脓胸相关淋巴瘤（PAL）是由慢性炎症发展而来的非霍奇金淋巴瘤。炎症病变中产生的自由基和氧化应激可引起DNA损伤，从而为淋巴瘤的发生提供基础。共济失调毛细血管扩张突变 (ATM) 以及 ATM 和 Rad3 相关 (ATR) 基因是 DNA 损伤的反应基因，因此在 8 个 PAL 细胞系和 5 个病例的临床样本中检查了这些基因在 PAL 淋巴瘤发生中的潜在参与。在八个 PAL 系中的五个中检测到 ATM 突变。除一种突变外，所有突变均影响磷脂酰肌醇 3-激酶结构域，表明 ATM 基因发生功能丧失突变。在八个品系中的两个中发现了 ATR 杂合突变；一个是错义，另一个是截断突变。 PAL 临床样本中的五分之二也检测到了 ATR 突变。具有ATR突变的PAL细胞表现出电离辐射（IR）诱导的DNA双链断裂（DSB）或紫外线（UV）诱导的DNA单链断裂（SSB）的修复延迟或取消，并且表现出p53积累缺陷和G1-S期细胞周期检查点失败。这些发现表明，ATR 基因突变导致 DNA DSB 和 SSB 修复失败，提示 ATM 和 ATR 基因突变在 PAL 淋巴瘤发生中的作用。
Pyothorax- associated lymphoma ( PAL) is non- Hodgkin's lymphoma that develops from chronic inflammation. Free radicals and oxidative stress generated in the inflammatory lesions could cause DNA damage and thus provide a basis for lymphomagenesis. Ataxia- telangiectasia mutated ( ATM) and ATM and Rad3- related ( ATR) genes are responsive genes for DNA damage, therefore potential involvement of these genes in PAL lymphomagenesis was examined in eight PAL cell lines and clinical samples from five cases. ATM mutations were detected in five of eight PAL lines. All but one of these mutations affected the phosphatidylinositol 3- kinase domain, indicating the loss- of- function mutation of ATM gene. Heterozygous mutations of ATR were found in two of eight lines; one a missense and the other a truncation mutation. ATR mutations were also detected in two of five cases in clinical samples from PAL. PAL cells with ATR mutation showed a delay or abrogation in repair for ionizing radiation ( IR)- induced DNA double- strand breaks ( DSBs) or ultraviolet ( UV)induced DNA single- strand breaks ( SSBs), and exhibited a defect in p53 accumulation and failure in cell cycle checkpoint at G1 - S phase. These findings showed that mutations of ATR gene result in failure for DNA DSB and SSB repair, suggesting the role of ATM and ATR gene mutations in PAL lymphomagenesis.