Revaud Déborah, Martins Luis M, Boussin François D, Sabatier Laure, Desmaze Chantal
Laboratoire de Radiopathologie, Institut de Radiobiologie Cellulaire et Moléculaire CEA-DSV, Université Paris VII UMR 967, Fontenay-aux-Roses, France.
Chromosoma. 2011 Jun;120(3):309-19. doi: 10.1007/s00412-011-0313-1. Epub 2011 Feb 26.
Interstitial telomeric sequences (ITSs) in hamster cells are hot spots for spontaneous and induced chromosome aberrations (CAs). Most data on ITS instability to date have been obtained in DNA repair-proficient cells. The classical non-homologous end joining repair pathway (C-NHEJ), which is the principal double strand break (DSB) repair mechanism in mammalian cells, is thought to restore the morphologically correct chromosome structure. The production of CAs thus involves DNA-PKcs-independent repair pathways. In our current study, we investigated the participation of DNA-PKcs from the C-NHEJ pathway in the repair of spontaneous or radiation-induced DSBs in ITSs using wild-type and DNA-PKcs mutant Chinese hamster ovary cells. Our data demonstrate that DNA-PKcs stabilizes spontaneous DSBs within ITSs from the chromosome 9 long arm, leading to the formation of terminal deletions. In addition, we show that DNA-PKcs-dependent C-NHEJ is employed following radiation-induced DSBs in other ITSs and restores morphologically correct chromosomes, whereas DNA-PKcs independent mechanisms co-exist in DNA-PKcs proficient cells leading to an excess of CAs within ITSs.
仓鼠细胞中的间质端粒序列（ITSs）是自发和诱导染色体畸变（CAs）的热点区域。迄今为止，关于ITS不稳定性的大多数数据都是在DNA修复功能正常的细胞中获得的。经典的非同源末端连接修复途径（C-NHEJ）是哺乳动物细胞中主要的双链断裂（DSB）修复机制，被认为可以恢复形态上正确的染色体结构。因此，CAs的产生涉及不依赖DNA-PKcs的修复途径。在我们目前的研究中，我们使用野生型和DNA-PKcs突变的中国仓鼠卵巢细胞，研究了C-NHEJ途径中的DNA-PKcs在修复ITS中自发或辐射诱导的DSB中的作用。我们的数据表明，DNA-PKcs可稳定9号染色体长臂ITS内的自发DSB，导致末端缺失的形成。此外，我们还表明，在其他ITS中辐射诱导DSB后，会采用依赖DNA-PKcs的C-NHEJ来恢复形态上正确的染色体，而在DNA-PKcs功能正常的细胞中，存在不依赖DNA-PKcs的机制，导致ITS内出现过多的CAs。
