对小鼠和人类癌症的遗传学研究证实 BCL11B 是一种单倍体不足的肿瘤抑制基因。矛盾的是，BCL11B 在一些人类癌症中过度表达，其敲低是合成致死的。我们在使用 DNA 糖基化酶 NTHL1 进行的邻近依赖性生物素化筛选中鉴定了 BCL11B 蛋白。体外 DNA 修复测定表明，BCL11B 和缺乏转录调控潜力的小型重组 BCL11B213-560 蛋白均可刺激两种碱基切除修复 (BER) 酶：NTHL1 和 Pol β 的酶活性。在细胞中，BCL11B 被迅速招募到激光微照射引起的 DNA 损伤部位。 BCL11B 敲除会延迟氧化 DNA 损伤的修复，而 BCL11B213-560 的异位表达会加速氧化 DNA 损伤的修复。 TK6 类淋巴母细胞中的一个 BCL11B 等位基因失活会导致自发突变率和辐射诱导突变率增加。反过来，BCL11B213-560 的异位表达通过减少 DNA 损伤和细胞衰老，与细胞转化中的 RAS 癌基因协同作用。这些发现表明 BCL11B 作为 BER 辅助因子发挥作用，保护正常细胞免于发生突变。矛盾的是，它还能使癌细胞存活下来，否则癌细胞会因活性氧生成增加而导致氧化 DNA 损伤而发生衰老或凋亡。© 作者 2023。由牛津大学出版社代表 Nucleic Acids 出版研究。

Genetic studies in mice and human cancers established BCL11B as a haploinsufficient tumor suppressor gene. Paradoxically, BCL11B is overexpressed in some human cancers where its knockdown is synthetic lethal. We identified the BCL11B protein in a proximity-dependent biotinylation screen performed with the DNA glycosylase NTHL1. In vitro DNA repair assays demonstrated that both BCL11B and a small recombinant BCL11B213-560 protein lacking transcription regulation potential can stimulate the enzymatic activities of two base excision repair (BER) enzymes: NTHL1 and Pol β. In cells, BCL11B is rapidly recruited to sites of DNA damage caused by laser microirradiation. BCL11B knockdown delays, whereas ectopic expression of BCL11B213-560 accelerates, the repair of oxidative DNA damage. Inactivation of one BCL11B allele in TK6 lymphoblastoid cells causes an increase in spontaneous and radiation-induced mutation rates. In turn, ectopic expression of BCL11B213-560 cooperates with the RAS oncogene in cell transformation by reducing DNA damage and cellular senescence. These findings indicate that BCL11B functions as a BER accessory factor, safeguarding normal cells from acquiring mutations. Paradoxically, it also enables the survival of cancer cells that would otherwise undergo senescence or apoptosis due to oxidative DNA damage resulting from the elevated production of reactive oxygen species.© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.