POLQ suppresses genome instability and alterations in DNA repeat tract lengths.
POLQ suppresses genome instability and alterations in DNA repeat tract lengths.
复制标题
作者：
DNA聚合酶θ（POLQ）是连接DNA双链断裂的替代性非同源末端连接（ANHEJ）DNA修复途径的主要组分。利用端粒驱动的危机期间POLQ不足的独立模型，我们发现POLQ-/-细胞对危机诱导的生长减速具有抗性，尽管维持与野生型（WT）细胞相当的染色体间端粒融合频率。我们记录了较长的端粒POLQ-/-比WT细胞危机前和危机后，尽管总端粒侵蚀和融合率升高。从危机中出现的POLQ-/-细胞表现出减少的发生率克隆总染色体异常，根据增加的遗传异质性。POLQ缺陷细胞的端粒融合扩增子的高通量测序显示染色体间融合的频率显著升高，染色体内重组相应降低。在POLQ-/-细胞中检测到端粒融合与着丝粒α-卫星重复序列的长程相互作用，以及HSAT 2和HSAT 3卫星的扩增和核糖体DNA重复序列的收缩。结合POLQ-/-细胞的端粒长度的扩大，这些结果表明，迄今未实现的能力POLQ基因组内的重复序列的调控。我们的研究结果揭示了POLQ抑制剂在临床癌症干预中的疗效的新考虑，其中潜在的基因组不稳定后果可能驱动克隆进化和耐药性疾病。POLQ缺陷细胞显示改变的DNA重复序列长度和遗传异质性，但降低染色体内端粒融合频率。
DNA polymerase theta (POLQ) is a principal component of the alternative non-homologous end-joining (ANHEJ) DNA repair pathway that ligates DNA double-strand breaks. Utilizing independent models of POLQ insufficiency during telomere-driven crisis, we found that POLQ–/– cells are resistant to crisis-induced growth deceleration despite sustaining inter-chromosomal telomere fusion frequencies equivalent to wild-type (WT) cells. We recorded longer telomeres in POLQ–/– than WT cells pre- and post-crisis, notwithstanding elevated total telomere erosion and fusion rates. POLQ–/– cells emerging from crisis exhibited reduced incidence of clonal gross chromosomal abnormalities in accordance with increased genetic heterogeneity. High-throughput sequencing of telomere fusion amplicons from POLQ-deficient cells revealed significantly raised frequencies of inter-chromosomal fusions with correspondingly depreciated intra-chromosomal recombinations. Long-range interactions culminating in telomere fusions with centromere alpha-satellite repeats, as well as expansions in HSAT2 and HSAT3 satellite and contractions in ribosomal DNA repeats, were detected in POLQ–/– cells. In conjunction with the expanded telomere lengths of POLQ–/– cells, these results indicate a hitherto unrealized capacity of POLQ for regulation of repeat arrays within the genome. Our findings uncover novel considerations for the efficacy of POLQ inhibitors in clinical cancer interventions, where potential genome destabilizing consequences could drive clonal evolution and resistant disease. POLQ-deficient cells display altered DNA repeat tract lengths and genetic heterogeneity, but reduced intra-chromosomal telomere fusion frequencies.
影响因子：
14.9
作者：
Apte MS;Masuda H;Wheeler DL;Cooper JP
通讯作者：
Cooper JP