Metastasis suppressor NM23-H1 promotes repair of UV-induced DNA damage and suppresses UV-induced melanomagenesis.
Metastasis suppressor NM23-H1 promotes repair of UV-induced DNA damage and suppresses UV-induced melanomagenesis.
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DOI：
10.1158/0008-5472.can-11-1795
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发表时间：
2012-01-01
期刊：
影响因子：
11.2
通讯作者：
Kaetzel DM
中科院分区：
文献类型：
--
作者：
Jarrett SG;Novak M;Dabernat S;Daniel JY;Mellon I;Zhang Q;Harris N;Ciesielski MJ;Fenstermaker RA;Kovacic D;Slominski A;Kaetzel DM
转移抑制因子NM23-H1的表达减少与多种癌症的侵袭性形式有关。在这里，我们确定NM23-H1（在人类中称为H1亚型，在小鼠中称为M1）及其伴随的两种酶活性，3 ‘ -5 ’外切酶和核苷二磷酸激酶，是细胞对紫外线辐射（UVR）诱导的DNA损伤反应的新参与者。NM23-H1缺陷损害了总DNA聚合酶阻断病变的修复动力学和（6-4）光产物的核苷酸切除修复动力学。NM23-H1的激酶活性对于多色UVB/UVA (290-400 nm)-和UVC （254 nm）诱导的DNA损伤的快速修复至关重要，而其3 ‘ -5 ’外切酶活性在抑制uvr诱导的突变中起主导作用。与其在DNA修复中的作用一致，NM23-H1在细胞核中迅速易位到uvr诱导的（6-4）光产物DNA损伤位点。此外，NM23 -m1和NM23 -m2半合子转基因小鼠表现出uvr诱导的黑色素瘤和滤泡性基底囊肿形成，肿瘤相关黑素细胞侵入邻近真皮，这与体内NM23侵袭抑制活性的丧失一致。综上所述，我们的数据表明NM23异构体在限制突变和抑制uvr诱导的黑色素瘤形成中起着关键作用。
Reduced expression of the metastasis suppressor NM23-H1 is associated with aggressive forms of multiple cancers. Here, we establish that NM23-H1 (termed H1 isoform in human, M1 in mouse) and two of its attendant enzymatic activities, the 3′-5′ exonuclease and nucleoside diphosphate kinase, are novel participants in the cellular response to UV radiation (UVR)-induced DNA damage. NM23-H1 deficiency compromised the kinetics of repair for total DNA polymerase-blocking lesions and nucleotide excision repair of (6-4) photoproducts in vitro. Kinase activity of NM23-H1 was critical for rapid repair of both polychromatic UVB/UVA (290-400 nm)- and UVC (254 nm)-induced DNA damage, while its 3′-5′ exonuclease activity was dominant in the suppression of UVR-induced mutagenesis. Consistent with its role in DNA repair, NM23-H1 rapidly translocated to sites of UVR-induced (6-4) photoproduct DNA damage in the nucleus. In addition, transgenic mice hemizygous-null for nm23-m1 and nm23-m2 exhibited UVR-induced melanoma and follicular infundibular cyst formation, and tumor-associated melanocytes displayed invasion into adjacent dermis, consistent with loss of invasion-suppressing activity of NM23 in vivo. Taken together, our data demonstrate a critical role for NM23 isoforms in limiting mutagenesis and suppressing UVR-induced melanomagenesis.