A novel human AP endonuclease with conserved zinc-finger-like motifs involved in DNA strand break responses
A novel human AP endonuclease with conserved zinc-finger-like motifs involved in DNA strand break responses
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DOI：
10.1038/sj.emboj.7601663
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发表时间：
2007-04-18
期刊：
影响因子：
11.4
通讯作者：
Yasui, Akira
中科院分区：
文献类型：
--
作者：
Kanno, Shin-ichiro;Kuzuoka, Hiroyuki;Yasui, Akira
DNA损伤导致基因组不稳定和细胞死亡，但许多细胞对DNA损伤的反应仍然难以捉摸。我们在这里报告了一种人类蛋白质，PALF（PNK和APTX样FHA蛋白），具有FHA（叉头相关）结构域和新的锌指样CYR（半胱氨酸酪氨酸精氨酸）基序，参与对DNA损伤的反应。我们发现CYR基序广泛分布于高等真核生物的DNA修复蛋白中，并且PALF以及具有串联CYR基序的果蝇蛋白具有针对脱碱基位点和其他类型的碱基损伤的核酸内切酶和核酸外切酶活性。PALF在人细胞中以聚（ADP-核糖）聚合酶1（PARP 1）依赖性方式在单链断裂处快速积累。事实上，PALF直接与PARP 1相互作用，并且是其活化和细胞对甲基甲烷磺酸盐的抗性所必需的。PALF还与KU 86、LIGASEIV和磷酸化XRCC 4蛋白直接相互作用，并在突出的DNA末端具有内切/外切核酸酶活性。产生双链断裂的各种处理诱导PALF病灶的形成，其与γ H2 AX病灶完全一致。因此，PALF和CYR基序可能在高等真核生物的DNA修复中发挥重要作用。
DNA damage causes genome instability and cell death, but many of the cellular responses to DNA damage still remain elusive. We here report a human protein, PALF (PNK and APTX-like FHA protein), with an FHA (forkhead-associated) domain and novel zinc-finger-like CYR (cysteine tyrosine-arginine) motifs that are involved in responses to DNA damage. We found that the CYR motif is widely distributed among DNA repair proteins of higher eukaryotes, and that PALF, as well as a Drosophila protein with tandem CYR motifs, has endo- and exonuclease activities against abasic site and other types of base damage. PALF accumulates rapidly at single-strand breaks in a poly(ADP-ribose) polymerase 1 (PARP1)-dependent manner in human cells. Indeed, PALF interacts directly with PARP1 and is required for its activation and for cellular resistance to methyl-methane sulfonate. PALF also interacts directly with KU86, LIGASEIV and phosphorylated XRCC4 proteins and possesses endo/exonuclease activity at protruding DNA ends. Various treatments that produce double-strand breaks induce formation of PALF foci, which fully coincide with gamma H2AX foci. Thus, PALF and the CYR motif may play important roles in DNA repair of higher eukaryotes.