Onyango David O, Howard Sean M, Neherin Kashfia, Yanez Diana A, Stark Jeremy M
Department of Cancer Genetics and Epigenetics, 1500 E Duarte Rd., Duarte, CA 91010, USA.
Department of Cancer Genetics and Epigenetics, 1500 E Duarte Rd., Duarte, CA 91010, USA Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope, 1500 E Duarte Rd., Duarte, CA 91010, USA.
Nucleic Acids Res. 2016 Jul 8;44(12):5702-16. doi: 10.1093/nar/gkw275. Epub 2016 Apr 15.
We examined the influence of the tetratricopeptide repeat factor XAB2 on chromosomal break repair, and found that XAB2 promotes end resection that generates the 3' ssDNA intermediate for homologous recombination (HR). Namely, XAB2 is important for chromosomal double-strand break (DSB) repair via two pathways of HR that require end resection as an intermediate step, end resection of camptothecin (Cpt)-induced DNA damage, and RAD51 recruitment to ionizing radiation induced foci (IRIF), which requires end resection. Furthermore, XAB2 mediates specific aspects of the DNA damage response associated with end resection proficiency: CtIP hyperphosphorylation induced by Cpt and BRCA1 IRIF. XAB2 also promotes histone acetylation events linked to HR proficiency. From truncation mutation analysis, the capacity for XAB2 to promote HR correlates with its ability to form a complex with ISY1 and PRP19, which show a similar influence as XAB2 on HR. This XAB2 complex localizes to punctate structures consistent with interchromatin granules that show a striking adjacent-localization to the DSB marker γH2AX. In summary, we suggest that the XAB2 complex mediates DNA damage response events important for the end resection step of HR, and speculate that its adjacent-localization relative to DSBs marked by γH2AX is important for this function.
我们研究了四肽重复因子XAB2对染色体断裂修复的影响，发现XAB2促进末端切除，从而产生用于同源重组（HR）的3'单链DNA中间体。也就是说，XAB2对于通过HR的两条途径进行染色体双链断裂（DSB）修复很重要，这两条途径都需要末端切除作为中间步骤，包括喜树碱（Cpt）诱导的DNA损伤的末端切除，以及将RAD51募集到电离辐射诱导灶（IRIF），而这也需要末端切除。此外，XAB2介导与末端切除能力相关的DNA损伤反应的特定方面：Cpt诱导的CtIP过度磷酸化和BRCA1 IRIF。XAB2还促进与HR能力相关的组蛋白乙酰化事件。通过截短突变分析，XAB2促进HR的能力与其与ISY1和PRP19形成复合物的能力相关，这两者对HR的影响与XAB2相似。这种XAB2复合物定位于点状结构，与染色质间颗粒一致，这些颗粒与DSB标记γH2AX显示出惊人的相邻定位。总之，我们认为XAB2复合物介导了对HR末端切除步骤很重要的DNA损伤反应事件，并推测其相对于由γH2AX标记的DSB的相邻定位对该功能很重要。
