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BRCT Domain-Containing Protein PTIP Is Essential for Progression through Mitosis

机译：包含BRCT域的蛋白PTIP对于有丝分裂的进展至关重要

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摘要

The Pax transactivation domain-interacting protein (PTIP) is a large nuclear protein with multiple BRCT domains that was identified on the basis of its interaction with transcription factors of the Pax and Smad families. To address the function of PTIP during mouse development, we generated a constitutive null allele. Homozygous PTIP mutants are developmentally retarded, disorganized, and embryonic lethal by day 9.5 of embryonic development (E9.5). PTIP mutant cells appear to replicate DNA but show reduced levels of mitosis and widespread cell death by E8.5. DNA damage appears to precede nuclear condensation at E7.5, suggesting a defect in DNA repair. Neither embryonic fibroblast nor embryonic stem cells from PTIP mutants proliferate in culture, suggesting a fundamental defect in cell proliferation. Trophoblast cells from PTIP mutants are more sensitive to DNA-damaging agents. Condensation of chromatin and expression of phospho-histone H3 are also affected in PTIP mutants, and this may underlie the inability of PTIP mutants to progress through mitosis. Given the role of BRCT domain proteins in DNA repair and cell cycle control, we propose that PTIP is an essential element of the cell proliferation machinery, perhaps by functioning in the DNA repair pathways.
机译：Pax反式激活域相互作用蛋白（PTIP）是具有多个BRCT域的大核蛋白，其基于与Pax和Smad家族转录因子的相互作用而鉴定。为了解决PTIP在小鼠发育过程中的功能，我们生成了一个组成型无效等位基因。纯合子 PTIP 突变体在胚胎发育的第9.5天（E9.5）发育迟缓，杂乱无章，并具有致命的胚胎致死性。 PTIP 突变细胞似乎可以复制DNA，但有丝分裂水平降低，E8.5导致广泛的细胞死亡。 DNA损伤似乎先于E7.5的核凝结，表明DNA修复存在缺陷。 PTIP 突变体的胚胎成纤维细胞和胚胎干细胞均不会在培养物中增殖，这表明细胞增殖存在根本缺陷。来自 PTIP 突变体的滋养细胞对DNA损伤剂更敏感。在 PTIP 突变体中，染色质的浓缩和磷酸化组蛋白H3的表达也受到影响，这可能是 PTIP 突变体无法通过有丝分裂进行的基础。考虑到BRCT结构域蛋白在DNA修复和细胞周期控制中的作用，我们建议PTIP是细胞增殖机制的重要组成部分，可能是通过在DNA修复途径中起作用。

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