Philipps University Marburg, Institute of Molecular Biology and Tumor Research (IMT), Emil-Mannkopff-Strasse 2, D-35037 Marburg, Germany.
Biochem Soc Trans. 2010 Dec;38(6):1704-8. doi: 10.1042/BST0381704.
CHK2 (checkpoint kinase 2) and BRCA1 (breast cancer early-onset 1) are tumour-suppressor genes that have been implicated previously in the DNA damage response. Recently, we have identified CHK2 and BRCA1 as genes required for the maintenance of chromosomal stability and have shown that a Chk2-mediated phosphorylation of Brca1 is required for the proper and timely assembly of mitotic spindles. Loss of CHK2, BRCA1 or inhibition of its Chk2-mediated phosphorylation inevitably results in the transient formation of abnormal spindles that facilitate the establishment of faulty microtubule-kinetochore attachments associated with the generation of lagging chromosomes. Importantly, both CHK2 and BRCA1 are lost at very high frequency in aneuploid lung adenocarcinomas that are typically induced in knockout mice exhibiting chromosomal instability. Thus these results suggest novel roles for Chk2 and Brca1 in mitosis that might contribute to their tumour-suppressor functions.
CHK2（检查点激酶 2）和 BRCA1（乳腺癌早期发病 1）是肿瘤抑制基因，先前已被涉及到 DNA 损伤反应。最近，我们已经确定 CHK2 和 BRCA1 是维持染色体稳定性所必需的基因，并表明 Chk2 介导的 Brca1 磷酸化对于有丝分裂纺锤体的正确和及时组装是必需的。CHK2、BRCA1 的缺失或其 Chk2 介导的磷酸化的抑制不可避免地导致异常纺锤体的短暂形成，这有利于建立与滞后染色体产生相关的错误微管-动粒连接。重要的是，在通常在染色体不稳定的敲除小鼠中诱导的非整倍体肺腺癌中，CHK2 和 BRCA1 丢失的频率非常高。因此，这些结果表明 Chk2 和 Brca1 在有丝分裂中具有新的作用，可能有助于它们的肿瘤抑制功能。
