RUNX Poly(ADP-Ribosyl)ation and BLM Interaction Facilitate the Fanconi Anemia Pathway of DNA Repair
RUNX Poly(ADP-Ribosyl)ation and BLM Interaction Facilitate the Fanconi Anemia Pathway of DNA Repair
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DOI：
10.1016/j.celrep.2018.07.038
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发表时间：
2018-08-14
期刊：
影响因子：
8.8
通讯作者：
Ito, Yoshiaki
中科院分区：
文献类型：
--
作者：
Tay, Lavina Sierra;Krishnan, Vaidehi;Ito, Yoshiaki
Fanconi贫血(FA)途径是一个关键的基因组维持网络，它协调DNA链间交联链(ICL)的修复。肿瘤抑制基因RUNX1和RUNX3被证明通过控制FANCD2的DNA损伤依赖的染色质关联来调节FA途径，而不依赖于它们规范的转录活性。在进一步的生化表征中，我们证明了RUNX3是通过PARP依赖的聚(ADP-核糖基化)修饰的，这反过来又允许RUNX与缺乏转录相关RUNX共识基序的DNA修复结构结合。基于SILAC的质谱分析显示，即使在非应激细胞中，RUNX3与核心DNA修复复合体，包括PARP1，也有显著的关联。DNA损伤后，RUNX3和BLM之间的相互作用增加促进了FANCD2染色质的有效定位。乳腺癌的RUNX-Walker基序突变对DNA损伤诱导的PAR化造成损害，揭示了癌症中FA途径失活的潜在机制。我们的结果加强了新兴的范式，即RUNX蛋白是具有基因组把关功能的肿瘤抑制因子。
The Fanconi anemia (FA) pathway is a pivotal genome maintenance network that orchestrates the repair of DNA interstrand crosslinks (ICLs). The tumor suppressors RUNX1 and RUNX3 were shown to regulate the FA pathway independent of their canonical transcription activities, by controlling the DNA damage-dependent chromatin association of FANCD2. Here, in further biochemical characterization, we demonstrate that RUNX3 is modified by PARP-dependent poly(ADP-ribosyl)ation (PARylation), which in turn allows RUNX binding to DNA repair structures lacking transcription-related RUNX consensus motifs. SILAC-based mass spectrometric analysis revealed significant association of RUNX3 with core DNA repair complexes, including PARP1, even in unstressed cells. After DNA damage, the increased interaction between RUNX3 and BLM facilitates efficient FANCD2 chromatin localization. RUNX-Walker motif mutations from breast cancers are impaired for DNA damage-inducible PARylation, unveiling a potential mechanism for FA pathway inactivation in cancers. Our results reinforce the emerging paradigm that RUNX proteins are tumor suppressors with genome gatekeeper function.