Molecular and Cellular Biology Department, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Nucleic Acids Res. 2012 Aug;40(15):7358-67. doi: 10.1093/nar/gks407. Epub 2012 May 10.
Werner's syndrome (WS) and Bloom's syndrome (BS) are cancer predisposition disorders caused by loss of function of the RecQ helicases WRN or BLM, respectively. BS and WS are characterized by replication defects, hyperrecombination events and chromosomal aberrations, which are hallmarks of cancer. Inefficient replication of the G-rich telomeric strand contributes to chromosome aberrations in WS cells, demonstrating a link between WRN, telomeres and genomic stability. Herein, we provide evidence that BLM also contributes to chromosome-end maintenance. Telomere defects (TDs) are observed in BLM-deficient cells at an elevated frequency, which is similar to cells lacking a functional WRN helicase. Loss of both helicases exacerbates TDs and chromosome aberrations, indicating that BLM and WRN function independently in telomere maintenance. BLM localization, particularly its recruitment to telomeres, changes in response to replication dysfunction, such as in WRN-deficient cells or after aphidicolin treatment. Exposure to replication challenge causes an increase in decatenated deoxyribonucleic acid (DNA) structures and late-replicating intermediates (LRIs), which are visible as BLM-covered ultra-fine bridges (UFBs) in anaphase. A subset of UFBs originates from telomeric DNA and their frequency correlates with telomere replication defects. We propose that the BLM complex contributes to telomere maintenance through its activity in resolving LRIs.
Werner 综合征（WS）和 Bloom 综合征（BS）是由 RecQ 解旋酶 WRN 或 BLM 功能丧失分别引起的癌症易感性疾病。BS 和 WS 的特征是复制缺陷、超重组事件和染色体异常，这些都是癌症的标志。富含 G 的端粒链复制效率低下导致 WS 细胞中的染色体异常，这表明 WRN、端粒和基因组稳定性之间存在联系。在此，我们提供的证据表明，BLM 也有助于染色体末端的维持。BLM 缺陷细胞中端粒缺陷（TDs）的频率升高，类似于缺乏功能正常的 WRN 解旋酶的细胞。两种解旋酶的缺失都会加剧 TD 和染色体异常，表明 BLM 和 WRN 独立地发挥作用来维持端粒。BLM 的定位，特别是其对端粒的募集，会因复制功能障碍而改变，如在 WRN 缺陷细胞或阿霉素处理后。暴露于复制挑战会导致去连环脱氧核糖核酸（DNA）结构和晚期复制中间体（LRIs）的增加，这些在有丝分裂后期作为 BLM 覆盖的超微桥（UFB）可见。一部分 UFB 源自端粒 DNA，其频率与端粒复制缺陷相关。我们提出，BLM 复合物通过其在解决 LRIs 中的活性来促进端粒的维持。
