Nguyen Diu Tt, Voon Hsiao Phin J, Xella Barbara, Scott Caroline, Clynes David, Babbs Christian, Ayyub Helena, Kerry Jon, Sharpe Jacqueline A, Sloane-Stanley Jackie A, Butler Sue, Fisher Chris A, Gray Nicki E, Jenuwein Thomas, Higgs Douglas R, Gibbons Richard J
MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK.
Department of Biochemistry and Molecular Biology, The Biomedicine Discovery Institute, Monash University, Clayton, Vic., Australia.
EMBO Rep. 2017 Jun;18(6):914-928. doi: 10.15252/embr.201643078. Epub 2017 May 9.
ATRX is a chromatin remodelling factor found at a wide range of tandemly repeated sequences including telomeres (TTAGGG) ATRX mutations are found in nearly all tumours that maintain their telomeres via the alternative lengthening of telomere (ALT) pathway, and ATRX is known to suppress this pathway. Here, we show that recruitment of ATRX to telomeric repeats depends on repeat number, orientation and, critically, on repeat transcription. Importantly, the transcribed telomeric repeats form RNA-DNA hybrids (R-loops) whose abundance correlates with the recruitment of ATRX Here, we show loss of ATRX is also associated with increased R-loop formation. Our data suggest that the presence of ATRX at telomeres may have a central role in suppressing deleterious DNA secondary structures that form at transcribed telomeric repeats, and this may account for the increased DNA damage, stalling of replication and homology-directed repair previously observed upon loss of ATRX function.
ATRX是一种染色质重塑因子，存在于包括端粒（TTAGGG）在内的多种串联重复序列中。几乎所有通过端粒替代延长（ALT）途径维持其端粒的肿瘤中都发现了ATRX突变，并且已知ATRX可抑制该途径。在这里，我们表明ATRX募集到端粒重复序列取决于重复序列的数量、方向，关键还取决于重复序列的转录。重要的是，转录的端粒重复序列形成RNA-DNA杂交体（R环），其丰度与ATRX的募集相关。在这里，我们表明ATRX的缺失也与R环形成增加有关。我们的数据表明，端粒处ATRX的存在可能在抑制转录的端粒重复序列处形成的有害DNA二级结构中起核心作用，这可能解释了先前在ATRX功能丧失时观察到的DNA损伤增加、复制停滞和同源定向修复。
