Lin Shiaw-Yih, Rai Rekha, Li Kaiyi, Xu Zhi-Xiang, Elledge Stephen J
Department of Molecular Therapeutics, University of Texas M. D. Anderson Cancer Center, Houston, TX 77054, USA.
Proc Natl Acad Sci U S A. 2005 Oct 18;102(42):15105-9. doi: 10.1073/pnas.0507722102. Epub 2005 Oct 10.
BRIT1 [BRCT-repeat inhibitor of hTERT expression], a repressor of human telomerase function, is implicated in cellular immortalization. Here, we find that BRIT1 acts as a regulator of both the intra-S and G2/M checkpoints. When BRIT1 expression is depleted, cells lose the ionizing radiation (IR)-induced cell cycle arrest and become IR sensitive. BRIT1 is a chromatin-associated protein that forms irradiation-induced nuclear foci that colocalize with gamma-H2AX foci. BRIT1 is also required for the expression of both BRCA1 and the checkpoint kinase Chk1 and phosphorylation of Nbs1. Thus, the checkpoint defects in the absence of BRIT1 are likely to result from its regulation of Nbs1, BRCA1, and Chk1. BRIT1 is identical to the recently discovered MCPH1 gene, found mutant in patients with primary microcephaly. The ataxia telangiectasia mutated-Rad3 related (ATR)-Chk1 pathway is defective in Seckel syndrome, another microcephaly disorder. We propose that the microcephaly observed in patients with MCPH1 deficiencies is due to disruption of the ATR-BRCA1-Chk1 signaling pathway that is also disrupted in Seckel syndrome patients.
BRIT1[人端粒酶逆转录酶（hTERT）表达的BRCT重复序列抑制剂]，一种人类端粒酶功能的抑制因子，与细胞永生化有关。在此，我们发现BRIT1作为S期内和G2/M期关卡的调节因子发挥作用。当BRIT1表达缺失时，细胞失去电离辐射（IR）诱导的细胞周期停滞并变得对IR敏感。BRIT1是一种与染色质相关的蛋白质，可形成与γ-H2AX焦点共定位的辐射诱导核焦点。BRIT1也是BRCA1和关卡激酶Chk1表达以及Nbs1磷酸化所必需的。因此，在没有BRIT1的情况下关卡缺陷可能是由于其对Nbs1、BRCA1和Chk1的调节所致。BRIT1与最近发现的MCPH1基因相同，在原发性小头畸形患者中发现该基因发生突变。共济失调毛细血管扩张症突变-Rad3相关（ATR）-Chk1通路在另一种小头畸形疾病Seckel综合征中存在缺陷。我们提出，在MCPH1缺陷患者中观察到的小头畸形是由于ATR-BRCA1-Chk1信号通路的破坏，而该通路在Seckel综合征患者中也被破坏。
